<?xml version="1.0" encoding="UTF-8" standalone="no"?>
<!DOCTYPE article PUBLIC "-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" "journalpublishing.dtd">
<article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" article-type="review-article">
<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Cardiovasc. Med.</journal-id>
<journal-title>Frontiers in Cardiovascular Medicine</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Cardiovasc. Med.</abbrev-journal-title>
<issn pub-type="epub">2297-055X</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fcvm.2021.715903</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Cardiovascular Medicine</subject>
<subj-group>
<subject>Mini Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>The Innate Immune cGAS-STING-Pathway in Cardiovascular Diseases &#x02013; A Mini Review</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name><surname>Rech</surname> <given-names>Lavinia</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<uri xlink:href="http://loop.frontiersin.org/people/1086439/overview"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name><surname>Rainer</surname> <given-names>Peter P.</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<xref ref-type="corresp" rid="c001"><sup>&#x0002A;</sup></xref>
<uri xlink:href="http://loop.frontiersin.org/people/712656/overview"/>
</contrib>
</contrib-group>
<aff id="aff1"><sup>1</sup><institution>Division of Cardiology, Department of Internal Medicine, Medical University of Graz</institution>, <addr-line>Graz</addr-line>, <country>Austria</country></aff>
<aff id="aff2"><sup>2</sup><institution>BioTechMed Graz</institution>, <addr-line>Graz</addr-line>, <country>Austria</country></aff>
<author-notes>
<fn fn-type="edited-by"><p>Edited by: Lisandra de Castro Br&#x000E1;s, East Carolina University, United States</p></fn>
<fn fn-type="edited-by"><p>Reviewed by: Nazareno Paolocci, Johns Hopkins University, United States; Giulio Agnetti, Johns Hopkins University, United States</p></fn>
<corresp id="c001">&#x0002A;Correspondence: Peter P. Rainer <email>peter.rainer&#x00040;medunigraz.at</email></corresp>
<fn fn-type="other" id="fn001"><p>This article was submitted to Cardiovascular Biologics and Regenerative Medicine, a section of the journal Frontiers in Cardiovascular Medicine</p></fn></author-notes>
<pub-date pub-type="epub">
<day>26</day>
<month>07</month>
<year>2021</year>
</pub-date>
<pub-date pub-type="collection">
<year>2021</year>
</pub-date>
<volume>8</volume>
<elocation-id>715903</elocation-id>
<history>
<date date-type="received">
<day>27</day>
<month>05</month>
<year>2021</year>
</date>
<date date-type="accepted">
<day>01</day>
<month>07</month>
<year>2021</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#x000A9; 2021 Rech and Rainer.</copyright-statement>
<copyright-year>2021</copyright-year>
<copyright-holder>Rech and Rainer</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p></license>
</permissions>
<abstract><p>Inflammation plays a central role in cardiovascular diseases (CVD). One pathway under investigation is the innate immune DNA sensor cyclic GMP-AMP synthase (cGAS) and its downstream receptor stimulator of interferon genes (STING). cGAS-STING upregulates type I interferons in response to pathogens. Recent studies show that also self-DNA may activate cGAS-STING, for instance, DNA released from nuclei or mitochondria during obesity or myocardial infarction. Here, we focus on emerging evidence describing the interaction of cGAS-STING with cardiovascular risk factors and disease. We also touch on translational therapeutic opportunities and potential further investigations.</p></abstract>
<kwd-group>
<kwd>STING</kwd>
<kwd>interferon</kwd>
<kwd>DAMPs</kwd>
<kwd>cardiovascular</kwd>
<kwd>inflammation</kwd>
<kwd>cGAS</kwd>
</kwd-group>
<contract-num rid="cn001">I 4168-B</contract-num>
<contract-sponsor id="cn001">Austrian Science Fund<named-content content-type="fundref-id">10.13039/501100002428</named-content></contract-sponsor>
<contract-sponsor id="cn002">&#x000D6;sterreichische Kardiologische Gesellschaft<named-content content-type="fundref-id">10.13039/501100015797</named-content></contract-sponsor>
<counts>
<fig-count count="2"/>
<table-count count="0"/>
<equation-count count="0"/>
<ref-count count="94"/>
<page-count count="8"/>
<word-count count="5635"/>
</counts>
</article-meta>
</front>
<body>
<sec sec-type="intro" id="s1">
<title>Introduction</title>
<p>Cardiovascular diseases (CVD) are one of the large health problems in our societies. The 2015 incidence for CVD in the European Society of Cardiology member countries was 11 million people with a prevalence of around 83.5 million (<xref ref-type="bibr" rid="B1">1</xref>). CVDs are the major global cause of death. Worldwide, more than 17 million people die from CVD each year (<xref ref-type="bibr" rid="B2">2</xref>, <xref ref-type="bibr" rid="B3">3</xref>), 4 million of which in Europe (<xref ref-type="bibr" rid="B2">2</xref>). The relation between inflammatory and immune phenomena and the pathophysiology of CVD is receiving increasing attention recently. Its role in disease progression is evident in several conditions (<xref ref-type="bibr" rid="B3">3</xref>&#x02013;<xref ref-type="bibr" rid="B5">5</xref>). For example, immune phenomena comprising both innate and adaptive responses are central in the development of atherosclerosis (<xref ref-type="bibr" rid="B6">6</xref>) and a landmark clinical trial demonstrated for the first time in 2017 that specifically targeting inflammation reduces cardiovascular events in high-risk subjects (<xref ref-type="bibr" rid="B7">7</xref>).</p>
<p>Inflammation and immune phenomena are also intricately involved in myocardial infarction healing and the progression of heart failure (<xref ref-type="bibr" rid="B8">8</xref>, <xref ref-type="bibr" rid="B9">9</xref>). Early myocardial infarction remodeling is a wound healing response with the massive influx of myeloid cells from extra-cardiac reservoirs (<xref ref-type="bibr" rid="B10">10</xref>). These innate immune cells clear necrosis and pave the way for the establishment of a functional scar. Exuberant responses, e.g., after inhibiting regulatory cytokines such as TGF-&#x003B2;, are detrimental, and preclinical trials demonstrate the benefit of suppressing these (<xref ref-type="bibr" rid="B11">11</xref>, <xref ref-type="bibr" rid="B12">12</xref>). However, clinical trials that sought to translate this to clinical use failed (<xref ref-type="bibr" rid="B13">13</xref>). Inflammatory processes are not only detrimental in injured tissues. In fact, they are often a requisite for repair and regeneration. The key is the right balance of proinflammatory and antiinflammatory responses in terms of magnitude and timing (<xref ref-type="bibr" rid="B12">12</xref>, <xref ref-type="bibr" rid="B14">14</xref>). For instance, macrophages can be proinflammatory (M1 like) and required to clear damaged tissue, while pro-reparative M2 like macrophages mitigate inflammatory responses and are essential for ensuing healing processes (<xref ref-type="bibr" rid="B15">15</xref>, <xref ref-type="bibr" rid="B16">16</xref>). In chronic heart failure, proinflammatory cytokines such as IL-1, IL-6, and TNF&#x003B1; are elevated and may contribute to disease progression (<xref ref-type="bibr" rid="B17">17</xref>), however, clinical studies targeting cytokines such as TGF&#x003B1; in heart failure patients failed in the past (<xref ref-type="bibr" rid="B18">18</xref>).</p>
</sec>
<sec id="s2">
<title>Innate Immunity and the cGAS-Sting Pathway</title>
<p>The innate immune system is our first-line defense and consists of humoral and cellular parts. Cellular components are phagocytes like neutrophils, eosinophils, and macrophages, as well as natural killer cells and dendritic cells (<xref ref-type="bibr" rid="B19">19</xref>, <xref ref-type="bibr" rid="B20">20</xref>). The humoral system includes the complement system and natural antibodies as well as cytokines like interferons (IFNs), interleukins (ILs), tumor necrosis factors (TNFs), and transforming growth factors (TGFs) (<xref ref-type="bibr" rid="B20">20</xref>&#x02013;<xref ref-type="bibr" rid="B22">22</xref>). Triggers initiating inflammation are pathogen-associated molecular patterns (PAMPs) derived from infectious agents, or non-infectious damage-associated molecular patterns (DAMPs). These molecular patterns can consist of different components like cell wall components, proteoglycans, or nucleic acids. DNA e.g., can originate from extracellular sources such as viruses, bacteria, or dying cells. However, DNA can also be derived from intracellular sources such as damaged nuclei or mitochondria. What these sources have in common is that DNA is present in compartments where it is out-of-place. DNA sensors are, for instance, the Toll-like receptor 9 (TLR9), absent in melanoma 2 (AIM2), or interferon gamma-induced 16 (IFI16) (<xref ref-type="bibr" rid="B23">23</xref>). cGAS is another example for a DNA sensor.</p>
<p>cGAS is a 63kDa protein predominantly localized in the cytoplasm during the cell cycle&#x00027;s interphase (<xref ref-type="bibr" rid="B24">24</xref>). It was initially described as a defense mechanism against viral and bacterial infections by binding foreign DNA and transforming ATP and GTP to the second messenger cyclic-GMP-AMP (cGAMP) (<xref ref-type="fig" rid="F1">Figure 1</xref>) (<xref ref-type="bibr" rid="B25">25</xref>&#x02013;<xref ref-type="bibr" rid="B36">36</xref>). cGAMP activates the STING receptor (<xref ref-type="bibr" rid="B36">36</xref>&#x02013;<xref ref-type="bibr" rid="B38">38</xref>). STING is a receptor protein with three isoforms ranging from 9&#x02013;34 kDa and is localized at the endoplasmic reticulum (<xref ref-type="bibr" rid="B39">39</xref>). STING activates the TANK-binding kinase 1 (TBK1), which phosphorylates the transcription factor interferon releasing factor 3 (IRF3) (<xref ref-type="bibr" rid="B35">35</xref>&#x02013;<xref ref-type="bibr" rid="B37">37</xref>). Ultimately, IRF3 induces the transcription of type I interferons (<xref ref-type="bibr" rid="B25">25</xref>, <xref ref-type="bibr" rid="B37">37</xref>), which in turn activate several signaling cascades including activation of the IFN-&#x003B1; receptor 1 (IFNAR1) and the transcription of IFN-stimulated genes (ISGs) (<xref ref-type="bibr" rid="B40">40</xref>, <xref ref-type="bibr" rid="B41">41</xref>).</p>
<fig id="F1" position="float">
<label>Figure 1</label>
<caption><p>Overview of the cGAS-STING pathway and inhibitors.</p></caption>
<graphic xlink:href="fcvm-08-715903-g0001.tif"/>
</fig>
<p>Regulatory mechanisms are necessary to attenuate excessive proinflammatory stimulation. This is also true for the cGAS-STING pathway. For instance, cytosolic deoxyribonuclease degrades cytosolic DNA and ensures that minute amounts of free DNA do not trigger the full inflammatory cascade (<xref ref-type="bibr" rid="B42">42</xref>). Additionally, an intact cell&#x00027;s compartmentalization restricts nuclear or mitochondrial DNA sensing by cytosolic sensors (<xref ref-type="bibr" rid="B42">42</xref>). However, the regulatory capacity is limited. Genomic instability and nucleic damage can release DNA in considerable amounts into the cytosolic compartment activating cGAS (<xref ref-type="bibr" rid="B36">36</xref>, <xref ref-type="bibr" rid="B38">38</xref>, <xref ref-type="bibr" rid="B43">43</xref>). ER stress also actives STING and IRF3 (<xref ref-type="bibr" rid="B31">31</xref>, <xref ref-type="bibr" rid="B44">44</xref>) and promotes autophagy in stressed cells, e.g., through direct interaction of cGAS with Beclin-1(<xref ref-type="bibr" rid="B31">31</xref>, <xref ref-type="bibr" rid="B45">45</xref>). STING activated T-cells can further induce a type I IFN response eliciting apoptosis (<xref ref-type="bibr" rid="B46">46</xref>). Interestingly, even in T cell-derived cancer cells, this process is still functional and represents a therapeutic approach (<xref ref-type="bibr" rid="B47">47</xref>). Similarly, STING may induce apoptosis in malignant B cells (<xref ref-type="bibr" rid="B48">48</xref>). Activating the cGAS-STING pathway also improves the outcome of solid tumors, for instance in metastatic breast cancer, by enhancing the immune response against tumor cells (<xref ref-type="bibr" rid="B49">49</xref>, <xref ref-type="bibr" rid="B50">50</xref>).</p>
<p>Another area where cGAS-STING is under investigation is infectious disease. For instance, virus infections like hepatitis B (<xref ref-type="bibr" rid="B51">51</xref>), Dengue (<xref ref-type="bibr" rid="B52">52</xref>), and HIV (<xref ref-type="bibr" rid="B31">31</xref>, <xref ref-type="bibr" rid="B38">38</xref>) or bacterial infections like tuberculosis (<xref ref-type="bibr" rid="B53">53</xref>) and Streptococcus pyogenes infections (<xref ref-type="bibr" rid="B38">38</xref>).</p>
<p>An increased amount of self-DNA released into the cytosol by autoimmune diseases activates the cGAS-STING pathway as well, e.g., in Systemic Lupus Erythematosus or Aicardi-Gouti&#x000E8;res syndrome (<xref ref-type="bibr" rid="B31">31</xref>, <xref ref-type="bibr" rid="B34">34</xref>, <xref ref-type="bibr" rid="B43">43</xref>, <xref ref-type="bibr" rid="B54">54</xref>, <xref ref-type="bibr" rid="B55">55</xref>). Another autoinflammatory disease without an increased amount of self-DNA is the STING-associated vasculopathy with onset in infancy (SAVI) with gain-of-function mutations in the STING gene (<xref ref-type="bibr" rid="B56">56</xref>).</p>
</sec>
<sec id="s3">
<title>Evidence for Involvement of the cGAS-Sting Pathway in Cardiovascular Risk Factors and Disease</title>
<p>Self-DNA can activate cGAS-STING in non-communicable, non-immune disorders such as CVD. Here, we give a concise overview of evidence linking CVD risk factors and disease to cGAS-STING (<xref ref-type="fig" rid="F2">Figure 2</xref>).</p>
<fig id="F2" position="float">
<label>Figure 2</label>
<caption><p>CVDs and risk factors associated with cytosolic DNA sensing.</p></caption>
<graphic xlink:href="fcvm-08-715903-g0002.tif"/>
</fig>
<sec>
<title>Risk Factors</title>
<sec>
<title>Smoking</title>
<p>Liu et al. (<xref ref-type="bibr" rid="B57">57</xref>) showed that side-steam smoke exposure (SSE), a model for second-hand smoking (SHS), reduced fractional shortening (FS) in mice and increased left ventricular (LV) mass. Additionally, they investigated these effects on mice haploinsufficient for the autophagy protein Beclin 1 (Becn<sup>&#x0002B;/&#x02212;</sup>). They found no difference between wild-type (WT) mice and Becn<sup>&#x0002B;/&#x02212;</sup> without SSE, but a significant reduction in FS and an increase in LV mass in Becn<sup>&#x0002B;/&#x02212;</sup> with SSE. On the cellular level, myocyte hypertrophy was present, myocardial TNF&#x003B1; and IL-1&#x003B2; increased, and cardiomyocyte peak shortening was reduced. This was associated with an increase of cGAS and STING protein expression, suggesting that this pathway is involved in the inflammatory process of SHS in WT and Becn<sup>&#x0002B;/&#x02212;</sup> mice and that this is exacerbated with impaired autophagy. Furthermore, the authors tested the cGAS inhibitor (PF-06928215) and STING inhibitor (Astin C) in their study. In WT mice with SSE, the inhibitors improved peak shortening significantly, while this effect was lost in Becn<sup>&#x0002B;/&#x02212;</sup> mice (<xref ref-type="bibr" rid="B57">57</xref>). Chronic ozone exposure, which mimics smoke-induced chronic obstructive pulmonary disease (COPD) and induces reactive oxygen species (ROS) and mitochondrial damage, may also be associated with the cGAS-STING signaling in humans (<xref ref-type="bibr" rid="B58">58</xref>).</p>
</sec>
<sec>
<title>Obesity</title>
<p>Another major risk factor for CVDs is obesity. Obesity is associated with endothelial inflammation (<xref ref-type="bibr" rid="B59">59</xref>) and induces proinflammatory responses in M1 macrophages, e.g., through elevated levels of palmitic acid (PA) in the blood (<xref ref-type="bibr" rid="B60">60</xref>). Mao et al. (<xref ref-type="bibr" rid="B61">61</xref>) investigated the influence of PA on cardiovascular endothelia and STING&#x00027;s role in this interaction. <italic>In-vitro</italic> experiments in human aortic endothelial cells demonstrate PA-induced mitochondrial damage and release of mitochondrial DNA (mtDNA) into the cytosol leading to cGAS STING pathway activation and IFN production. Silencing STING or IRF responses <italic>via</italic> small interfering RNA (siRNA) attenuates this response. These results were reiterated <italic>in-vivo</italic> as well. Wild-type mice on a high-fat diet (HFD) had a significant increase of IRF3 in adipose tissue and the aortic wall, which was reduced in STING-deficient (STING<sup>gt/gt</sup>) mice (<xref ref-type="bibr" rid="B61">61</xref>).</p>
<p>A recent study from Gong et al. supports cGAS-STING&#x00027;s effect on HFD associated cardiovascular dysfunction. They showed that WT mice with HFD had significantly reduced FS <italic>in-vivo</italic>, peak shorting in isolated cardiomyocytes, and cardiomyocyte hypertrophy. This was accompanied by elevation of TNF&#x003B1;, IL-1&#x003B2;, STING, and cGAS. Deletion of <italic>Akt2</italic> and <italic>Ampk</italic>&#x003B1;<italic>2</italic> (double knock-out, DKO), decreased phosphorylation of Unc-51 like autophagy activation kinase (ULK1) (<xref ref-type="bibr" rid="B62">62</xref>), which phosphorylates Beclin1 and thereby induces autophagy (<xref ref-type="bibr" rid="B63">63</xref>). Furthermore, cGAS/STING activation on HFD was amplified in DKO (<xref ref-type="bibr" rid="B62">62</xref>).</p>
</sec>
<sec>
<title>Aging</title>
<p>Inflammageing describes low-grade, chronic, and sterile inflammation that occurs with aging and is associated with CVDs (<xref ref-type="bibr" rid="B64">64</xref>). One trigger for this inflammatory process is the degeneration of DNA during aging.</p>
<p>Quan et al. (<xref ref-type="bibr" rid="B65">65</xref>) demonstrated that cGAS-STING regulates the senescence-associated secretory phenotype (SASP). SASP in aged hearts is primed by an increase in proinflammatory cytokines like IL-1&#x003B2;, IL-6, and IL-8, and release of mtDNA into the cytosol may induce SASP <italic>via</italic> cGAS-STING. Circulating mtDNA associated with age increases inflammatory SASP in aged hearts (<xref ref-type="bibr" rid="B66">66</xref>, <xref ref-type="bibr" rid="B67">67</xref>).</p>
<p>Interestingly, patients suffering from the accelerated aging disease Hutchinson Gilford Progeria Syndrome (HGPS) often die from CVDs like myocardial infarction (MI) or stroke (<xref ref-type="bibr" rid="B68">68</xref>) and HGPS is associated with amplified interferon responses potentially <italic>via</italic> the cGAS-STING pathway (<xref ref-type="bibr" rid="B69">69</xref>&#x02013;<xref ref-type="bibr" rid="B71">71</xref>). However, mutations can also be protective. The single nucleotide polymorphism (SNP) R293Q of the <italic>STING</italic> gene is protective in obesity-associated CVDs and other age-related diseases (<xref ref-type="bibr" rid="B72">72</xref>, <xref ref-type="bibr" rid="B73">73</xref>).</p>
</sec>
</sec>
<sec>
<title>Established CVD</title>
<sec>
<title>Heart Failure</title>
<p>Heart Failure (HF) is a clinical syndrome with symptoms and structural and/or functional cardiac abnormalities (<xref ref-type="bibr" rid="B68">68</xref>). It represents end stage disease in many CVDs like ischemia or hypertension.</p>
<p>In a model of non-ischemic pressure-overload induced heart failure (transverse aortic constriction, TAC) exhibiting hypertrophy, cardiac dysfunction, and fibrosis expression of STING, IFN&#x003B1; and IFN&#x003B2; were increased (<xref ref-type="bibr" rid="B74">74</xref>). In STING knock-out (STING-KO) mice, levels returned to baseline levels (<xref ref-type="bibr" rid="B74">74</xref>). Neonatal rat cardiomyocytes treated with angiotensin II had increased levels of STING, IFN&#x003B1;, and IFN&#x003B2;. STING inhibition <italic>via</italic> siRNA resulted in a significant reduction of IL-6, IL-1&#x003B2;, TNF&#x003B1;, IFN&#x003B1;, and IFN&#x003B2; in these cells. Increased levels of STING, IFN&#x003B1;, and IFN&#x003B2; were also seen in human samples of dilative and hypertrophic cardiomyopathies (<xref ref-type="bibr" rid="B74">74</xref>).</p>
<p>Another study confirmed these findings: the expression levels of cGAS, STING, IFN, and the IFN induced chemokines CXCL10, IFIT3, and ISG15 were significantly increased 3 days after TAC (<xref ref-type="bibr" rid="B75">75</xref>). Silencing cGAS <italic>via</italic> adeno-associated virus 9 (AAV9) resulted in a significant decrease of LV remodeling and fibrosis (<xref ref-type="bibr" rid="B75">75</xref>).</p>
</sec>
<sec>
<title>Myocardial Infarction</title>
<p>Two independent groups investigated the relevance of cGAS-STING in myocardial infarction healing. They demonstrate increased IFN&#x003B2;1 expression and IRF3 phosphorylation and an increase in the expression levels of CXCL10, IRF7, STING, and cGAS after myocardial infarction (<xref ref-type="bibr" rid="B76">76</xref>, <xref ref-type="bibr" rid="B77">77</xref>). This was attenuated by using knockout models for pathway members such as cGAS, STING, or IRF3. Interestingly, cGAS knock-out (cGAS<sup>&#x02212;/&#x02212;</sup>) did not reduce the universal proinflammatory cytokines IL-1&#x003B2;, TNF&#x003B1;, and IL-6 (<xref ref-type="bibr" rid="B76">76</xref>).</p>
<p>By using fluorescence reporter tagged cells, parabiosis experiments, and scRNAseq King et al. (<xref ref-type="bibr" rid="B77">77</xref>) demonstrated that cardiomyocyte cell death after MI leads to recruitment of interferon-inducible cells (IFNICs) with increased expression of IRF3-dependent genes from the blood to the heart and they identify these IFNICs as monocyte-derived cardiac macrophages that phagocytose cell debris. Disruption of pathway activation <italic>via</italic> genetic or pharmacologic means improves outcomes.</p>
<p>Cao et al. (<xref ref-type="bibr" rid="B76">76</xref>) treated WT and cGAS<sup>&#x02212;/&#x02212;</sup> human macrophages with IFN stimulatory DNA. As expected, cGAS<sup>&#x02212;/&#x02212;</sup> macrophages produced no cGAS and also no CXCL10 (<xref ref-type="bibr" rid="B76">76</xref>). CXCL10 was expressed in WT macrophages and associated with M1-like polarization. In contrast, M2 marker expression like CD163, IL-10, and CCL17 was increased in cGAS<sup>&#x02212;/&#x02212;</sup> animals (<xref ref-type="bibr" rid="B76">76</xref>).</p>
<p>Both groups observed improved outcomes in cGAS<sup>&#x02212;/&#x02212;</sup> mice compared to WT in terms of LV function and survival (<xref ref-type="bibr" rid="B76">76</xref>, <xref ref-type="bibr" rid="B77">77</xref>), although, the survival benefit was more pronounced in INFAR and IRF3 knockout animals. IFNAR neutralization <italic>via</italic> antibodies mirrored survival and functional benefit.</p>
<p>Interestingly, Cao et al. showed increased myofibroblast activation and collagen deposition in cGAS<sup>&#x02212;/&#x02212;</sup> mice after MI and propose this enhances functional scar generation.</p>
<p>Cao et al. also provide data demonstrating high myocardial levels of cGAS and CXCL10 in human end stage ischemic heart failure patients that are decreased back to near normal levels by unloading the left ventricle by means of mechanical circulatory support <italic>via</italic> left ventricular assist devices (LVADs).</p>
</sec>
<sec>
<title>Stroke</title>
<p>Li et al. (<xref ref-type="bibr" rid="B78">78</xref>) showed that the cGAS-STING pathway is also involved in stroke in an <italic>in-vivo</italic> model with middle cerebral artery occlusion (MCAO). They observed increased levels of cGAS and STING in the infarcted brain area. Using a small synthetic oligodeoxynucleotide, A151 (TTAGGG), which inhibits cGAS, this was reduced to the levels of sham-operated mice. Additionally, A151 reduced IL-1&#x003B2; levels, reduced infarct size and improved cognitive function (<xref ref-type="bibr" rid="B78">78</xref>).</p>
</sec>
<sec>
<title>Cardiovascular and Systemic Infection</title>
<p>Li et al. (<xref ref-type="bibr" rid="B79">79</xref>) described upregulation of STING and phosphorylated IRF3 in an <italic>in vitro</italic> model of sepsis induced cardiomyopathy (SIC) using neonatal rat cardiomyocytes. Treating cells with siRNA against STING resulted in a decrease in IRF3 phosphorylation. In an <italic>in vivo</italic> model of SIC using LPS injection STING-KO reduced CK-MB, IL-1&#x003B2;, and TNF&#x003B1; levels and improved EF, FS, and survival. Likewise, other investigators found that the small cGAS inhibitor molecule RU.521 improved LPS induced SIC (IRF3 phosphorylation, IL-1&#x003B2;, IL-6, TNF&#x003B1; expression, apoptosis, left ventricular function, and survival) (<xref ref-type="bibr" rid="B80">80</xref>). Lastly, selenium supplementation appeared to ameliorate LPS-induced SIC <italic>via</italic> STING (<xref ref-type="bibr" rid="B81">81</xref>).</p>
<p>In Chagas cardiomyopathy, Choudhuri et al. showed that extracellular vesicles from Trypanosoma cruzi infected cells lead to increased levels of IL-1&#x003B2;, IL-6, and TNF&#x003B1; in macrophages. Using different inhibitors, including the cGAS inhibitor PF-06928215, they detected a significant decrease in the levels of IL-1&#x003B2;, IL-6c, and TNF&#x003B1; (<xref ref-type="bibr" rid="B82">82</xref>).</p>
<p>Further, there is speculation that COVID-19 infection may lead to prolonged cGAS-STING pathway activation in leucocytes (<xref ref-type="bibr" rid="B83">83</xref>) and increased leucocyte infiltration was present in the majority COVID-19 patient&#x00027;s hearts in an autopsy studie (<xref ref-type="bibr" rid="B84">84</xref>).</p>
</sec>
<sec>
<title>Radiation Injury</title>
<p>Radiation produces DNA damage, which can be sensed in the cytosol by cGAS (<xref ref-type="bibr" rid="B85">85</xref>). Phillipp et al. (<xref ref-type="bibr" rid="B86">86</xref>) studied the effect of radiation on cultured human coronary artery endothelial cells. With increasing radiation up to 10 Gy, the expression levels of STING and ISG15 increased continuously after 1 week as well as ISG15 and cGAS up to a dose of 2 Gy. This may have clinical implications as radiation therapy for breast cancer may result in up to 20 Gy delivered to the left anterior descending coronary artery (LAD) (<xref ref-type="bibr" rid="B87">87</xref>).</p>
</sec>
</sec>
</sec>
<sec id="s4">
<title>Conclusion and Outlook</title>
<p>cGAS-STING is involved in the pathophysiology of cardiovascular disease and risk factors. This ranges from conditions with cell death and massive release of DAMPs such as myocardial infarction or stroke to chronic conditions where inflammatory responses are mildly increased over longer periods such as heart failure. This may have translational implications, as pharmacologic agents are available and have been tested for non-cardiovascular diseases. Inhibitors of cGAS include PF-06928215, A151, RU.521, J014, G140, or X6 (<xref ref-type="bibr" rid="B80">80</xref>, <xref ref-type="bibr" rid="B88">88</xref>&#x02013;<xref ref-type="bibr" rid="B90">90</xref>). Direct STING inhibition also seems promising (<xref ref-type="bibr" rid="B91">91</xref>) and antagonists include Astin C, C-176, C178, and H-151 (<xref ref-type="bibr" rid="B88">88</xref>, <xref ref-type="bibr" rid="B92">92</xref>, <xref ref-type="bibr" rid="B93">93</xref>). However, potential adverse effects need to be studied. As cGAS and STING agonists are used for cancer and viral infection treatments (<xref ref-type="bibr" rid="B48">48</xref>&#x02013;<xref ref-type="bibr" rid="B51">51</xref>), inhibition may promote these conditions. Furthermore, pathways are more complex and promiscuous than mentioned here, and inhibitors targeting other molecules may impact cGAS-STING too, for instance the ALK inhibitor LDK378 (<xref ref-type="bibr" rid="B94">94</xref>).</p>
<p>In conclusion, CVD and risk factors modulate cGAS-STING and this may contribute to disease progression. Targeting pathway members may be useful to attenuate excessive inflammation, e.g., ischemic injury to the heart or brain.</p>
</sec>
<sec id="s5">
<title>Author Contributions</title>
<p>LR and PR wrote the manuscript. All authors contributed to the article and approved the submitted version.</p>
</sec>
<sec sec-type="COI-statement" id="conf1">
<title>Conflict of Interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec sec-type="disclaimer" id="s6">
<title>Publisher&#x00027;s Note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
</body>
<back>
<ack><p>Figures have been created with <ext-link ext-link-type="uri" xlink:href="https://BioRender.com">BioRender.com</ext-link>.</p>
</ack>
<ref-list>
<title>References</title>
<ref id="B1">
<label>1.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Timmis</surname> <given-names>A</given-names></name> <name><surname>Townsend</surname> <given-names>N</given-names></name> <name><surname>Gale</surname> <given-names>CP</given-names></name> <name><surname>Torbica</surname> <given-names>A</given-names></name> <name><surname>Lettino</surname> <given-names>M</given-names></name> <name><surname>Petersen</surname> <given-names>SE</given-names></name> <etal/></person-group>. <article-title>European Society of cardiology: cardiovascular disease statistics 2019</article-title>. <source>Eur Heart J.</source> (<year>2020</year>) <volume>41</volume>:<fpage>12</fpage>&#x02013;<lpage>85</lpage>. <pub-id pub-id-type="doi">10.1093/eurheartj/ehz859</pub-id><pub-id pub-id-type="pmid">32049279</pub-id></citation></ref>
<ref id="B2">
<label>2.</label>
<citation citation-type="book"><person-group person-group-type="author"><name><surname>Wilkins</surname> <given-names>E</given-names></name> <name><surname>Wilson</surname> <given-names>L</given-names></name> <name><surname>Wickramasinghe</surname> <given-names>K</given-names></name> <name><surname>Bhatnagar</surname> <given-names>P</given-names></name> <name><surname>Leal</surname> <given-names>J</given-names></name> <name><surname>Luengo-Fernandez</surname> <given-names>R</given-names></name> <etal/></person-group>. <source>European Cardiovascular Disease Statistics 2017</source>. <publisher-loc>Brussels</publisher-loc>: <publisher-name>European Heart Network AISBL</publisher-name> (<year>2017</year>).<pub-id pub-id-type="pmid">29190377</pub-id></citation></ref>
<ref id="B3">
<label>3.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Golia</surname> <given-names>E</given-names></name> <name><surname>Limongelli</surname> <given-names>G</given-names></name> <name><surname>Natale</surname> <given-names>F</given-names></name> <name><surname>Fimiani</surname> <given-names>F</given-names></name> <name><surname>Maddaloni</surname> <given-names>V</given-names></name> <name><surname>Pariggiano</surname> <given-names>I</given-names></name> <etal/></person-group>. <article-title>Inflammation and cardiovascular disease: from pathogenesis to therapeutic target</article-title>. <source>Curr Atheroscler Rep.</source> (<year>2014</year>) <volume>16</volume>:<fpage>435</fpage>. <pub-id pub-id-type="doi">10.1007/s11883-014-0435-z</pub-id><pub-id pub-id-type="pmid">25037581</pub-id></citation></ref>
<ref id="B4">
<label>4.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Libby</surname> <given-names>P</given-names></name> <name><surname>Ridker</surname> <given-names>PM</given-names></name> <name><surname>Hansson</surname> <given-names>GK</given-names></name></person-group>. <article-title>Inflammation in atherosclerosis: from pathophysiology to practice</article-title>. <source>J Am Coll Cardiol.</source> (<year>2009</year>) <volume>54</volume>:<fpage>2129</fpage>&#x02013;<lpage>38</lpage>. <pub-id pub-id-type="doi">10.1016/j.jacc.2009.09.009</pub-id></citation></ref>
<ref id="B5">
<label>5.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Taleb</surname> <given-names>S</given-names></name></person-group>. <article-title>Inflammation in atherosclerosis</article-title>. <source>Arch Cardiovasc Dis.</source> (<year>2016</year>) <volume>109</volume>:<fpage>708</fpage>&#x02013;<lpage>15</lpage>. <pub-id pub-id-type="doi">10.1016/j.acvd.2016.04.002</pub-id></citation></ref>
<ref id="B6">
<label>6.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wolf</surname> <given-names>D</given-names></name> <name><surname>Ley</surname> <given-names>K</given-names></name></person-group>. <article-title>Immunity and inflammation in atherosclerosis</article-title>. <source>Circ Res.</source> (<year>2019</year>) <volume>124</volume>:<fpage>315</fpage>&#x02013;<lpage>27</lpage>. <pub-id pub-id-type="doi">10.1161/CIRCRESAHA.118.313591</pub-id></citation></ref>
<ref id="B7">
<label>7.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ridker</surname> <given-names>PM</given-names></name> <name><surname>Everett</surname> <given-names>BM</given-names></name> <name><surname>Thuren</surname> <given-names>T</given-names></name> <name><surname>MacFadyen</surname> <given-names>JG</given-names></name> <name><surname>Chang</surname> <given-names>WH</given-names></name> <name><surname>Ballantyne</surname> <given-names>C</given-names></name> <etal/></person-group>. <article-title>Antiinflammatory therapy with canakinumab for atherosclerotic disease</article-title>. <source>N Engl J Med.</source> (<year>2017</year>) <volume>377</volume>:<fpage>1119</fpage>&#x02013;<lpage>31</lpage>. <pub-id pub-id-type="doi">10.1056/NEJMoa1707914</pub-id><pub-id pub-id-type="pmid">28845751</pub-id></citation></ref>
<ref id="B8">
<label>8.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Shirazi</surname> <given-names>LF</given-names></name> <name><surname>Bissett</surname> <given-names>J</given-names></name> <name><surname>Romeo</surname> <given-names>F</given-names></name> <name><surname>Mehta</surname> <given-names>JL</given-names></name></person-group>. <article-title>Role of inflammation in heart failure</article-title>. <source>Curr Atheroscler Rep.</source> (<year>2017</year>) <volume>19</volume>:<fpage>27</fpage>. <pub-id pub-id-type="doi">10.1007/s11883-017-0660-3</pub-id></citation></ref>
<ref id="B9">
<label>9.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Frangogiannis</surname> <given-names>NG</given-names></name></person-group>. <article-title>The inflammatory response in myocardial injury, repair, and remodelling</article-title>. <source>Nat Rev Cardiol.</source> (<year>2014</year>) <volume>11</volume>:<fpage>255</fpage>&#x02013;<lpage>65</lpage>. <pub-id pub-id-type="doi">10.1038/nrcardio.2014.28</pub-id><pub-id pub-id-type="pmid">24663091</pub-id></citation></ref>
<ref id="B10">
<label>10.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Nahrendorf</surname> <given-names>M</given-names></name> <name><surname>Swirski</surname> <given-names>FK</given-names></name> <name><surname>Aikawa</surname> <given-names>E</given-names></name> <name><surname>Stangenberg</surname> <given-names>L</given-names></name> <name><surname>Wurdinger</surname> <given-names>T</given-names></name> <name><surname>Figueiredo</surname> <given-names>J-L</given-names></name> <etal/></person-group>. <article-title>The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions</article-title>. <source>J Exp Med.</source> (<year>2007</year>) <volume>204</volume>:<fpage>3037</fpage>&#x02013;<lpage>47</lpage>. <pub-id pub-id-type="doi">10.1084/jem.20070885</pub-id><pub-id pub-id-type="pmid">18025128</pub-id></citation></ref>
<ref id="B11">
<label>11.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Frantz</surname> <given-names>S</given-names></name> <name><surname>Hu</surname> <given-names>K</given-names></name> <name><surname>Adamek</surname> <given-names>A</given-names></name> <name><surname>Wolf</surname> <given-names>J</given-names></name> <name><surname>Sallam</surname> <given-names>A</given-names></name> <name><surname>Maier</surname> <given-names>SKG</given-names></name> <etal/></person-group>. <article-title>Transforming growth factor beta inhibition increases mortality and left ventricular dilatation after myocardial infarction</article-title>. <source>Basic Res Cardiol.</source> (<year>2008</year>) <volume>103</volume>:<fpage>485</fpage>&#x02013;<lpage>92</lpage>. <pub-id pub-id-type="doi">10.1007/s00395-008-0739-7</pub-id><pub-id pub-id-type="pmid">18651091</pub-id></citation></ref>
<ref id="B12">
<label>12.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Epelman</surname> <given-names>S</given-names></name> <name><surname>Liu</surname> <given-names>PP</given-names></name> <name><surname>Mann</surname> <given-names>DL</given-names></name></person-group>. <article-title>Role of innate and adaptive immune mechanisms in cardiac injury and repair</article-title>. <source>Nat Rev Immunol.</source> (<year>2015</year>) <volume>15</volume>:<fpage>117</fpage>&#x02013;<lpage>29</lpage>. <pub-id pub-id-type="doi">10.1038/nri3800</pub-id><pub-id pub-id-type="pmid">25614321</pub-id></citation></ref>
<ref id="B13">
<label>13.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Silverman</surname> <given-names>HS</given-names></name> <name><surname>Pfeifer</surname> <given-names>MP</given-names></name></person-group>. <article-title>Relation between use of antiinflammatory agents and left ventricular free wall rupture during acute myocardial infarction</article-title>. <source>Am J Cardiol.</source> (<year>1987</year>) <volume>59</volume>:<fpage>363</fpage>&#x02013;<lpage>4</lpage>. <pub-id pub-id-type="doi">10.1016/0002-9149(87)90817-4</pub-id></citation></ref>
<ref id="B14">
<label>14.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ong</surname> <given-names>S-B</given-names></name> <name><surname>Hern&#x000E1;ndez-Res&#x000E9;ndiz</surname> <given-names>S</given-names></name> <name><surname>Crespo-Avilan</surname> <given-names>GE</given-names></name> <name><surname>Mukhametshina</surname> <given-names>RT</given-names></name> <name><surname>Kwek</surname> <given-names>X-Y</given-names></name> <name><surname>Cabrera-Fuentes</surname> <given-names>HA</given-names></name> <etal/></person-group>. <article-title>Inflammation following acute myocardial infarction: multiple players, dynamic roles, and novel therapeutic opportunities</article-title>. <source>Pharmacol Ther.</source> (<year>2018</year>) <volume>186</volume>:<fpage>73</fpage>&#x02013;<lpage>87</lpage>. <pub-id pub-id-type="doi">10.1016/j.pharmthera.2018.01.001</pub-id><pub-id pub-id-type="pmid">29330085</pub-id></citation></ref>
<ref id="B15">
<label>15.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>de Couto</surname> <given-names>G</given-names></name></person-group>. <article-title>Macrophages in cardiac repair: environmental cues and therapeutic strategies</article-title>. <source>Exp Mol Med</source>. (<year>2019</year>) <volume>51</volume>:<fpage>1</fpage>&#x02013;<lpage>10</lpage>. <pub-id pub-id-type="doi">10.1038/s12276-019-0269-4</pub-id><pub-id pub-id-type="pmid">31857583</pub-id></citation></ref>
<ref id="B16">
<label>16.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Das</surname> <given-names>A</given-names></name> <name><surname>Sinha</surname> <given-names>M</given-names></name> <name><surname>Datta</surname> <given-names>S</given-names></name> <name><surname>Abas</surname> <given-names>M</given-names></name> <name><surname>Chaffee</surname> <given-names>S</given-names></name> <name><surname>Sen</surname> <given-names>CK</given-names></name> <etal/></person-group>. <article-title>Monocyte and macrophage plasticity in tissue repair and regeneration</article-title>. <source>Am J Pathol.</source> (<year>2015</year>) <volume>185</volume>:<fpage>2596</fpage>&#x02013;<lpage>606</lpage>. <pub-id pub-id-type="doi">10.1016/j.ajpath.2015.06.001</pub-id><pub-id pub-id-type="pmid">26118749</pub-id></citation></ref>
<ref id="B17">
<label>17.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Adamo</surname> <given-names>L</given-names></name> <name><surname>Rocha-Resende</surname> <given-names>C</given-names></name> <name><surname>Prabhu</surname> <given-names>SD</given-names></name> <name><surname>Mann</surname> <given-names>DL</given-names></name></person-group>. <article-title>Reappraising the role of inflammation in heart failure</article-title>. <source>Nat Rev Cardiol.</source> (<year>2020</year>) <volume>17</volume>:<fpage>269</fpage>&#x02013;<lpage>85</lpage>. <pub-id pub-id-type="doi">10.1038/s41569-019-0315-x</pub-id><pub-id pub-id-type="pmid">33712807</pub-id></citation></ref>
<ref id="B18">
<label>18.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Chung</surname> <given-names>ES</given-names></name> <name><surname>Packer</surname> <given-names>M</given-names></name> <name><surname>Lo</surname> <given-names>KH</given-names></name> <name><surname>Fasanmade</surname> <given-names>AA</given-names></name> <name><surname>Willerson</surname> <given-names>JT</given-names></name></person-group>. <article-title>Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial</article-title>. <source>Circulation.</source> (<year>2003</year>) <volume>107</volume>:<fpage>3133</fpage>&#x02013;<lpage>40</lpage>. <pub-id pub-id-type="doi">10.1161/01.CIR.0000077913.60364.D2</pub-id><pub-id pub-id-type="pmid">12796126</pub-id></citation></ref>
<ref id="B19">
<label>19.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Beutler</surname> <given-names>B</given-names></name></person-group>. <article-title>Innate immunity: an overview</article-title>. <source>Mol Immunol.</source> (<year>2004</year>) <volume>40</volume>:<fpage>845</fpage>&#x02013;<lpage>59</lpage>. <pub-id pub-id-type="doi">10.1016/j.molimm.2003.10.005</pub-id></citation></ref>
<ref id="B20">
<label>20.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Riera Romo</surname> <given-names>M</given-names></name> <name><surname>P&#x000E9;rez-Mart&#x000ED;nez</surname> <given-names>D</given-names></name> <name><surname>Castillo Ferrer</surname> <given-names>C</given-names></name></person-group>. <article-title>Innate immunity in vertebrates: an overview</article-title>. <source>Immunology.</source> (<year>2016</year>) <volume>148</volume>:<fpage>125</fpage>&#x02013;<lpage>39</lpage>. <pub-id pub-id-type="doi">10.1111/imm.12597</pub-id></citation></ref>
<ref id="B21">
<label>21.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Tomar</surname> <given-names>N</given-names></name> <name><surname>De</surname> <given-names>RK</given-names></name></person-group>. <article-title>A brief outline of the immune system</article-title>. <source>Meth Mol Biol.</source> (<year>2014</year>) <volume>1184</volume>:<fpage>3</fpage>&#x02013;<lpage>12</lpage>. <pub-id pub-id-type="doi">10.1007/978-1-4939-1115-8_1</pub-id></citation></ref>
<ref id="B22">
<label>22.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Medzhitov</surname> <given-names>R</given-names></name></person-group>. <article-title>Origin and physiological roles of inflammation</article-title>. <source>Nature.</source> (<year>2008</year>) <volume>454</volume>:<fpage>428</fpage>&#x02013;<lpage>35</lpage>. <pub-id pub-id-type="doi">10.1038/nature07201</pub-id></citation></ref>
<ref id="B23">
<label>23.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Briard</surname> <given-names>B</given-names></name> <name><surname>Place</surname> <given-names>DE</given-names></name> <name><surname>Kanneganti</surname> <given-names>T-D</given-names></name></person-group>. <article-title>DNA sensing in the innate immune response</article-title>. <source>Physiology.</source> (<year>2020</year>) <volume>35</volume>:<fpage>112</fpage>&#x02013;<lpage>24</lpage>. <pub-id pub-id-type="doi">10.1152/physiol.00022.2019</pub-id><pub-id pub-id-type="pmid">33749478</pub-id></citation></ref>
<ref id="B24">
<label>24.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Zhong</surname> <given-names>L</given-names></name> <name><surname>Hu</surname> <given-names>M-M</given-names></name> <name><surname>Bian</surname> <given-names>L-J</given-names></name> <name><surname>Liu</surname> <given-names>Y</given-names></name> <name><surname>Chen</surname> <given-names>Q</given-names></name> <name><surname>Shu</surname> <given-names>H-B</given-names></name></person-group>. <article-title>Phosphorylation of cGAS by CDK1 impairs self-DNA sensing in mitosis</article-title>. <source>Cell Discov.</source> (<year>2020</year>) <volume>6</volume>:<fpage>26</fpage>. <pub-id pub-id-type="doi">10.1038/s41421-020-0162-2</pub-id><pub-id pub-id-type="pmid">33907180</pub-id></citation></ref>
<ref id="B25">
<label>25.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Sun</surname> <given-names>L</given-names></name> <name><surname>Wu</surname> <given-names>J</given-names></name> <name><surname>Du</surname> <given-names>F</given-names></name> <name><surname>Chen</surname> <given-names>X</given-names></name> <name><surname>Chen</surname> <given-names>ZJ</given-names></name></person-group>. <article-title>Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway</article-title>. <source>Science.</source> (<year>2013</year>) <volume>339</volume>:<fpage>786</fpage>&#x02013;<lpage>91</lpage>. <pub-id pub-id-type="doi">10.1126/science.1232458</pub-id><pub-id pub-id-type="pmid">23258413</pub-id></citation></ref>
<ref id="B26">
<label>26.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Schoggins</surname> <given-names>JW</given-names></name> <name><surname>MacDuff</surname> <given-names>DA</given-names></name> <name><surname>Imanaka</surname> <given-names>N</given-names></name> <name><surname>Gainey</surname> <given-names>MD</given-names></name> <name><surname>Shrestha</surname> <given-names>B</given-names></name> <name><surname>Eitson</surname> <given-names>JL</given-names></name> <etal/></person-group>. <article-title>Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity</article-title>. <source>Nature.</source> (<year>2014</year>) <volume>505</volume>:<fpage>691</fpage>&#x02013;<lpage>5</lpage>. <pub-id pub-id-type="doi">10.1038/nature12862</pub-id><pub-id pub-id-type="pmid">26153856</pub-id></citation></ref>
<ref id="B27">
<label>27.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Li</surname> <given-names>X-D</given-names></name> <name><surname>Wu</surname> <given-names>J</given-names></name> <name><surname>Gao</surname> <given-names>D</given-names></name> <name><surname>Wang</surname> <given-names>H</given-names></name> <name><surname>Sun</surname> <given-names>L</given-names></name> <name><surname>Chen</surname> <given-names>ZJ</given-names></name></person-group>. <article-title>Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects</article-title>. <source>Science.</source> (<year>2013</year>) <volume>341</volume>:<fpage>1390</fpage>&#x02013;<lpage>4</lpage>. <pub-id pub-id-type="doi">10.1126/science.1244040</pub-id><pub-id pub-id-type="pmid">23989956</pub-id></citation></ref>
<ref id="B28">
<label>28.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Collins</surname> <given-names>AC</given-names></name> <name><surname>Cai</surname> <given-names>H</given-names></name> <name><surname>Li</surname> <given-names>T</given-names></name> <name><surname>Franco</surname> <given-names>LH</given-names></name> <name><surname>Li</surname> <given-names>X-D</given-names></name> <name><surname>Nair</surname> <given-names>VR</given-names></name> <etal/></person-group>. <article-title>Cyclic GMP-AMP synthase is an innate immune DNA sensor for mycobacterium tuberculosis</article-title>. <source>Cell Host Microbe</source>. (<year>2015</year>) <volume>17</volume>:<fpage>820</fpage>&#x02013;<lpage>8</lpage>. <pub-id pub-id-type="doi">10.1016/j.chom.2015.05.005</pub-id><pub-id pub-id-type="pmid">26048137</pub-id></citation></ref>
<ref id="B29">
<label>29.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Civril</surname> <given-names>F</given-names></name> <name><surname>Deimling</surname> <given-names>T</given-names></name> <name><surname>Oliveira Mann</surname> <given-names>CC de</given-names></name> <name><surname>Ablasser</surname> <given-names>A</given-names></name> <name><surname>Moldt</surname> <given-names>M</given-names></name> <name><surname>Witte</surname> <given-names>G</given-names></name> <etal/></person-group>. <article-title>Structural mechanism of cytosolic DNA sensing by cGAS</article-title>. <source>Nature.</source> (<year>2013</year>) <volume>498</volume>:<fpage>332</fpage>&#x02013;<lpage>7</lpage>. <pub-id pub-id-type="doi">10.1038/nature12305</pub-id><pub-id pub-id-type="pmid">23722159</pub-id></citation></ref>
<ref id="B30">
<label>30.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wu</surname> <given-names>J</given-names></name> <name><surname>Sun</surname> <given-names>L</given-names></name> <name><surname>Chen</surname> <given-names>X</given-names></name> <name><surname>Du</surname> <given-names>F</given-names></name> <name><surname>Shi</surname> <given-names>H</given-names></name> <name><surname>Chen</surname> <given-names>C</given-names></name> <etal/></person-group>. <article-title>Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA</article-title>. <source>Science.</source> (<year>2013</year>) <volume>339</volume>:<fpage>826</fpage>&#x02013;<lpage>30</lpage>. <pub-id pub-id-type="doi">10.1126/science.1229963</pub-id><pub-id pub-id-type="pmid">28399655</pub-id></citation></ref>
<ref id="B31">
<label>31.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wan</surname> <given-names>D</given-names></name> <name><surname>Jiang</surname> <given-names>W</given-names></name> <name><surname>Hao</surname> <given-names>J</given-names></name></person-group>. <article-title>Research advances in how the cGAS-STING pathway controls the cellular inflammatory response</article-title>. <source>Front Immunol.</source> (<year>2020</year>) <volume>11</volume>:<fpage>615</fpage>. <pub-id pub-id-type="doi">10.3389/fimmu.2020.00615</pub-id><pub-id pub-id-type="pmid">32411126</pub-id></citation></ref>
<ref id="B32">
<label>32.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname> <given-names>H</given-names></name> <name><surname>Moura-Alves</surname> <given-names>P</given-names></name> <name><surname>Pei</surname> <given-names>G</given-names></name> <name><surname>Mollenkopf</surname> <given-names>H-J</given-names></name> <name><surname>Hurwitz</surname> <given-names>R</given-names></name> <name><surname>Wu</surname> <given-names>X</given-names></name> <etal/></person-group>. <article-title>cGAS facilitates sensing of extracellular cyclic dinucleotides to activate innate immunity</article-title>. <source>EMBO Rep.</source> (<year>2019</year>) <volume>20</volume>:<fpage>e46293</fpage>. <pub-id pub-id-type="doi">10.15252/embr.201846293</pub-id><pub-id pub-id-type="pmid">30872316</pub-id></citation></ref>
<ref id="B33">
<label>33.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Yang</surname> <given-names>H</given-names></name> <name><surname>Wang</surname> <given-names>H</given-names></name> <name><surname>Ren</surname> <given-names>J</given-names></name> <name><surname>Chen</surname> <given-names>Q</given-names></name> <name><surname>Chen</surname> <given-names>ZJ</given-names></name></person-group>. <article-title>cGAS is essential for cellular senescence</article-title>. <source>PNAS.</source> (<year>2017</year>) <volume>114</volume>:<fpage>E4612</fpage>&#x02013;<lpage>20</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.1705499114</pub-id></citation></ref>
<ref id="B34">
<label>34.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Cai</surname> <given-names>X</given-names></name> <name><surname>Chiu</surname> <given-names>Y-H</given-names></name> <name><surname>Chen</surname> <given-names>ZJ</given-names></name></person-group>. <article-title>The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling</article-title>. <source>Mol Cell.</source> (<year>2014</year>) <volume>54</volume>:<fpage>289</fpage>&#x02013;<lpage>96</lpage>. <pub-id pub-id-type="doi">10.1016/j.molcel.2014.03.040</pub-id><pub-id pub-id-type="pmid">24766893</pub-id></citation></ref>
<ref id="B35">
<label>35.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Paludan</surname> <given-names>SR</given-names></name> <name><surname>Bowie</surname> <given-names>AG</given-names></name></person-group>. <article-title>Immune sensing of DNA</article-title>. <source>Immunity.</source> (<year>2013</year>) <volume>38</volume>:<fpage>870</fpage>&#x02013;<lpage>80</lpage>. <pub-id pub-id-type="doi">10.1016/j.immuni.2013.05.004</pub-id></citation></ref>
<ref id="B36">
<label>36.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Chen</surname> <given-names>Q</given-names></name> <name><surname>Sun</surname> <given-names>L</given-names></name> <name><surname>Chen</surname> <given-names>ZJ</given-names></name></person-group>. <article-title>Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing</article-title>. <source>Nat Immunol.</source> (<year>2016</year>) <volume>17</volume>:<fpage>1142</fpage>&#x02013;<lpage>9</lpage>. <pub-id pub-id-type="doi">10.1038/ni.3558</pub-id><pub-id pub-id-type="pmid">27648547</pub-id></citation></ref>
<ref id="B37">
<label>37.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Banete</surname> <given-names>A</given-names></name> <name><surname>Seaver</surname> <given-names>K</given-names></name> <name><surname>Bakshi</surname> <given-names>D</given-names></name> <name><surname>Gee</surname> <given-names>K</given-names></name> <name><surname>Basta</surname> <given-names>S</given-names></name></person-group>. <article-title>On taking the STING out of immune activation</article-title>. <source>J Leukoc Biol.</source> <volume>103</volume>:<fpage>1189</fpage>&#x02013;<lpage>95</lpage>. (<year>2018</year>). <pub-id pub-id-type="doi">10.1002/JLB.2MIR0917-383R</pub-id><pub-id pub-id-type="pmid">29431896</pub-id></citation></ref>
<ref id="B38">
<label>38.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Barber</surname> <given-names>GN</given-names></name></person-group>. <article-title>STING: infection, inflammation, and cancer</article-title>. <source>Nat Rev Immunol.</source> (<year>2015</year>) <volume>15</volume>:<fpage>760</fpage>&#x02013;<lpage>70</lpage>. <pub-id pub-id-type="doi">10.1038/nri3921</pub-id></citation></ref>
<ref id="B39">
<label>39.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ishikawa</surname> <given-names>H</given-names></name> <name><surname>Barber</surname> <given-names>GN</given-names></name></person-group>. <article-title>STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling</article-title>. <source>Nature.</source> (<year>2008</year>) <volume>455</volume>:<fpage>674</fpage>&#x02013;<lpage>8</lpage>. <pub-id pub-id-type="doi">10.1038/nature07317</pub-id><pub-id pub-id-type="pmid">18724357</pub-id></citation></ref>
<ref id="B40">
<label>40.</label>
<citation citation-type="book"><person-group person-group-type="editor"><name><surname>Meager</surname> <given-names>A</given-names></name></person-group> editor. <source>The Interferons: Characterization and Application</source>. <publisher-loc>Weinheim</publisher-loc>: <publisher-name>Wiley-VCH</publisher-name> (<year>2006</year>). <pub-id pub-id-type="doi">10.1002/3527608206</pub-id></citation>
</ref>
<ref id="B41">
<label>41.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Schneider</surname> <given-names>WM</given-names></name> <name><surname>Chevillotte</surname> <given-names>MD</given-names></name> <name><surname>Rice</surname> <given-names>CM</given-names></name></person-group>. <article-title>Interferon-stimulated genes: a complex web of host defenses</article-title>. <source>Annu Rev Immunol.</source> (<year>2014</year>) <volume>32</volume>:<fpage>513</fpage>&#x02013;<lpage>45</lpage>. <pub-id pub-id-type="doi">10.1146/annurev-immunol-032713-120231</pub-id><pub-id pub-id-type="pmid">24555472</pub-id></citation></ref>
<ref id="B42">
<label>42.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ablasser</surname> <given-names>A</given-names></name> <name><surname>Chen</surname> <given-names>ZJ</given-names></name></person-group>. <article-title>cGAS in action: expanding roles in immunity and inflammation</article-title>. <source>Science.</source> (<year>2019</year>) <volume>363</volume>:<fpage>eaat8657</fpage>. <pub-id pub-id-type="doi">10.1126/science.aat8657</pub-id><pub-id pub-id-type="pmid">30846571</pub-id></citation></ref>
<ref id="B43">
<label>43.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Li</surname> <given-names>T</given-names></name> <name><surname>Chen</surname> <given-names>ZJ</given-names></name></person-group>. <article-title>The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer</article-title>. <source>J Exp Med.</source> (<year>2018</year>) <volume>215</volume>:<fpage>1287</fpage>&#x02013;<lpage>99</lpage>. <pub-id pub-id-type="doi">10.1084/jem.20180139</pub-id><pub-id pub-id-type="pmid">29622565</pub-id></citation></ref>
<ref id="B44">
<label>44.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname> <given-names>Y-P</given-names></name> <name><surname>Zeng</surname> <given-names>L</given-names></name> <name><surname>Tian</surname> <given-names>A</given-names></name> <name><surname>Bomkamp</surname> <given-names>A</given-names></name> <name><surname>Rivera</surname> <given-names>D</given-names></name> <name><surname>Gutman</surname> <given-names>D</given-names></name> <etal/></person-group>. <article-title>Endoplasmic reticulum stress regulates the innate immunity critical transcription factor IRF3</article-title>. <source>J Immunol.</source> (<year>2012</year>) <volume>189</volume>:<fpage>4630</fpage>&#x02013;<lpage>9</lpage>. <pub-id pub-id-type="doi">10.4049/jimmunol.1102737</pub-id><pub-id pub-id-type="pmid">23028052</pub-id></citation></ref>
<ref id="B45">
<label>45.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Liang</surname> <given-names>Q</given-names></name> <name><surname>Seo</surname> <given-names>GJ</given-names></name> <name><surname>Choi</surname> <given-names>YJ</given-names></name> <name><surname>Kwak</surname> <given-names>M-J</given-names></name> <name><surname>Ge</surname> <given-names>J</given-names></name> <name><surname>Rodgers</surname> <given-names>MA</given-names></name> <etal/></person-group>. <article-title>Crosstalk between the cGAS DNA sensor and Beclin-1 autophagy protein shapes innate antimicrobial immune responses</article-title>. <source>Cell Host Microb.</source> (<year>2014</year>) <volume>15</volume>:<fpage>228</fpage>&#x02013;<lpage>38</lpage>. <pub-id pub-id-type="doi">10.1016/j.chom.2014.01.009</pub-id><pub-id pub-id-type="pmid">24528868</pub-id></citation></ref>
<ref id="B46">
<label>46.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Larkin</surname> <given-names>B</given-names></name> <name><surname>Ilyukha</surname> <given-names>V</given-names></name> <name><surname>Sorokin</surname> <given-names>M</given-names></name> <name><surname>Buzdin</surname> <given-names>A</given-names></name> <name><surname>Vannier</surname> <given-names>E</given-names></name> <name><surname>Poltorak</surname> <given-names>A</given-names></name></person-group>. <article-title>Cutting edge: activation of STING in T cells induces type I IFN responses and cell death</article-title>. <source>J Immunol.</source> (<year>2017</year>) <volume>199</volume>:<fpage>397</fpage>&#x02013;<lpage>402</lpage>. <pub-id pub-id-type="doi">10.4049/jimmunol.1601999</pub-id><pub-id pub-id-type="pmid">28615418</pub-id></citation></ref>
<ref id="B47">
<label>47.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gulen</surname> <given-names>MF</given-names></name> <name><surname>Koch</surname> <given-names>U</given-names></name> <name><surname>Haag</surname> <given-names>SM</given-names></name> <name><surname>Schuler</surname> <given-names>F</given-names></name> <name><surname>Apetoh</surname> <given-names>L</given-names></name> <name><surname>Villunger</surname> <given-names>A</given-names></name> <etal/></person-group>. <article-title>Signalling strength determines proapoptotic functions of STING</article-title>. <source>Nat Commun.</source> (<year>2017</year>) <volume>8</volume>:<fpage>1</fpage>&#x02013;<lpage>10</lpage>. <pub-id pub-id-type="doi">10.1038/s41467-017-00573-w</pub-id><pub-id pub-id-type="pmid">28874664</pub-id></citation></ref>
<ref id="B48">
<label>48.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Tang</surname> <given-names>C-HA</given-names></name> <name><surname>Zundell</surname> <given-names>JA</given-names></name> <name><surname>Ranatunga</surname> <given-names>S</given-names></name> <name><surname>Lin</surname> <given-names>C</given-names></name> <name><surname>Nefedova</surname> <given-names>Y</given-names></name> <name><surname>Del Valle</surname> <given-names>JR</given-names></name> <etal/></person-group>. <article-title>Agonist-mediated activation of STING induces apoptosis in malignant B cells: single nucleotide polymorphisms of human STING can affect innate immune response to cyclic dinucleotides</article-title>. <source>Cancer Res.</source> (<year>2016</year>) <volume>76</volume>:<fpage>2137</fpage>&#x02013;<lpage>52</lpage>. <pub-id pub-id-type="doi">10.1158/0008-5472.CAN-15-1885</pub-id></citation></ref>
<ref id="B49">
<label>49.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Corrales</surname> <given-names>L</given-names></name> <name><surname>Gajewski</surname> <given-names>TF</given-names></name></person-group>. <article-title>Molecular pathways: targeting the stimulator of interferon genes (STING) in the immunotherapy of cancer</article-title>. <source>Clin Cancer Res.</source> (<year>2015</year>) <volume>21</volume>:<fpage>4774</fpage>&#x02013;<lpage>9</lpage>. <pub-id pub-id-type="doi">10.1158/1078-0432.CCR-15-1362</pub-id><pub-id pub-id-type="pmid">26373573</pub-id></citation></ref>
<ref id="B50">
<label>50.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Weiss</surname> <given-names>JM</given-names></name> <name><surname>Gu&#x000E9;rin</surname> <given-names>MV</given-names></name> <name><surname>Regnier</surname> <given-names>F</given-names></name> <name><surname>Renault</surname> <given-names>G</given-names></name> <name><surname>Galy-Fauroux</surname> <given-names>I</given-names></name> <name><surname>Vimeux</surname> <given-names>L</given-names></name> <etal/></person-group>. <article-title>The STING agonist DMXAA triggers a cooperation between T lymphocytes and myeloid cells that leads to tumor regression</article-title>. <source>Oncoimmunology.</source> (<year>2017</year>) <volume>6</volume>:<fpage>e1346765</fpage>. <pub-id pub-id-type="doi">10.1080/2162402X.2017.1346765</pub-id><pub-id pub-id-type="pmid">29123960</pub-id></citation></ref>
<ref id="B51">
<label>51.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Guo</surname> <given-names>F</given-names></name> <name><surname>Han</surname> <given-names>Y</given-names></name> <name><surname>Zhao</surname> <given-names>X</given-names></name> <name><surname>Wang</surname> <given-names>J</given-names></name> <name><surname>Liu</surname> <given-names>F</given-names></name> <name><surname>Xu</surname> <given-names>C</given-names></name> <etal/></person-group>. <article-title>STING agonists induce an innate antiviral immune response against Hepatitis B virus</article-title>. <source>Antimicrob Agents Chemother</source>. (<year>2015</year>) <volume>59</volume>:<fpage>1273</fpage>&#x02013;<lpage>81</lpage>. <pub-id pub-id-type="doi">10.1128/AAC.04321-14</pub-id><pub-id pub-id-type="pmid">25512416</pub-id></citation></ref>
<ref id="B52">
<label>52.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Aguirre</surname> <given-names>S</given-names></name> <name><surname>Luthra</surname> <given-names>P</given-names></name> <name><surname>Sanchez-Aparicio</surname> <given-names>MT</given-names></name> <name><surname>Maestre</surname> <given-names>AM</given-names></name> <name><surname>Patel</surname> <given-names>J</given-names></name> <name><surname>Lamothe</surname> <given-names>F</given-names></name> <etal/></person-group>. <article-title>Dengue virus NS2B protein targets cGAS for degradation and prevents mitochondrial DNA sensing during infection</article-title>. <source>Nat Microbiol.</source> (<year>2017</year>) <volume>2</volume>:<fpage>17037</fpage>. <pub-id pub-id-type="doi">10.1038/nmicrobiol.2017.37</pub-id><pub-id pub-id-type="pmid">28346446</pub-id></citation></ref>
<ref id="B53">
<label>53.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wiens</surname> <given-names>KE</given-names></name> <name><surname>Ernst</surname> <given-names>JD</given-names></name></person-group>. <article-title>The mechanism for type I interferon induction by mycobacterium tuberculosis is bacterial strain-Dependent</article-title>. <source>PLoS Pathog.</source> (<year>2016</year>) <volume>12</volume>:<fpage>e1005809</fpage>. <pub-id pub-id-type="doi">10.1371/journal.ppat.1005809</pub-id><pub-id pub-id-type="pmid">27500737</pub-id></citation></ref>
<ref id="B54">
<label>54.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gao</surname> <given-names>D</given-names></name> <name><surname>Li</surname> <given-names>T</given-names></name> <name><surname>Li</surname> <given-names>X-D</given-names></name> <name><surname>Chen</surname> <given-names>X</given-names></name> <name><surname>Li</surname> <given-names>Q-Z</given-names></name> <name><surname>Wight-Carter</surname> <given-names>M</given-names></name> <etal/></person-group>. <article-title>Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases</article-title>. <source>PNAS.</source> (<year>2015</year>) <volume>112</volume>:<fpage>E5699</fpage>&#x02013;<lpage>705</lpage>. <pub-id pub-id-type="doi">10.1073/pnas.1516465112</pub-id><pub-id pub-id-type="pmid">26371324</pub-id></citation></ref>
<ref id="B55">
<label>55.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>H&#x000E4;rtlova</surname> <given-names>A</given-names></name> <name><surname>Erttmann</surname> <given-names>SF</given-names></name> <name><surname>Am Raffi</surname> <given-names>F</given-names></name> <name><surname>Schmalz</surname> <given-names>AM</given-names></name> <name><surname>Resch</surname> <given-names>U</given-names></name> <name><surname>Anugula</surname> <given-names>S</given-names></name> <etal/></person-group>. <article-title>DNA damage primes the type I interferon system <italic>via</italic> the cytosolic DNA sensor STING to promote anti-microbial innate immunity</article-title>. <source>Immunity.</source> (<year>2015</year>) <volume>42</volume>:<fpage>332</fpage>&#x02013;<lpage>43</lpage>. <pub-id pub-id-type="doi">10.1016/j.immuni.2015.01.012</pub-id><pub-id pub-id-type="pmid">25692705</pub-id></citation></ref>
<ref id="B56">
<label>56.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname> <given-names>Y</given-names></name> <name><surname>Jesus</surname> <given-names>AA</given-names></name> <name><surname>Marrero</surname> <given-names>B</given-names></name> <name><surname>Yang</surname> <given-names>D</given-names></name> <name><surname>Ramsey</surname> <given-names>SE</given-names></name> <name><surname>Sanchez</surname> <given-names>GAM</given-names></name> <etal/></person-group>. <article-title>Activated STING in a vascular and pulmonary syndrome</article-title>. <source>N Engl J Med.</source> (<year>2014</year>) <volume>371</volume>:<fpage>507</fpage>&#x02013;<lpage>18</lpage>. <pub-id pub-id-type="doi">10.1056/NEJMoa1312625</pub-id><pub-id pub-id-type="pmid">25029335</pub-id></citation></ref>
<ref id="B57">
<label>57.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Liu</surname> <given-names>F</given-names></name> <name><surname>Liu</surname> <given-names>Y</given-names></name> <name><surname>Zhuang</surname> <given-names>Z</given-names></name> <name><surname>Ma</surname> <given-names>J</given-names></name> <name><surname>Xu</surname> <given-names>X</given-names></name> <name><surname>Zhang</surname> <given-names>W</given-names></name> <etal/></person-group>. <article-title>Beclin1 haploinsufficiency accentuates second-hand smoke exposure -induced myocardial remodeling and contractile dysfunction through a STING-mediated mechanism</article-title>. <source>J Mol Cell Cardiol</source>. (<year>2020</year>) <volume>148</volume>:<fpage>78</fpage>&#x02013;<lpage>88</lpage>. <pub-id pub-id-type="doi">10.1016/j.yjmcc.2020.08.016</pub-id><pub-id pub-id-type="pmid">32891637</pub-id></citation></ref>
<ref id="B58">
<label>58.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wiegman</surname> <given-names>CH</given-names></name> <name><surname>Li</surname> <given-names>F</given-names></name> <name><surname>Ryffel</surname> <given-names>B</given-names></name> <name><surname>Togbe</surname> <given-names>D</given-names></name> <name><surname>Chung</surname> <given-names>KF</given-names></name></person-group>. <article-title>Oxidative stress in ozone-induced chronic lung inflammation and emphysema: a facet of chronic obstructive pulmonary disease</article-title>. <source>Front. Immunol.</source> (<year>2020</year>) <volume>11</volume>:<fpage>1957</fpage>. <pub-id pub-id-type="doi">10.3389/fimmu.2020.01957</pub-id><pub-id pub-id-type="pmid">32983127</pub-id></citation></ref>
<ref id="B59">
<label>59.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Villaret</surname> <given-names>A</given-names></name> <name><surname>Galitzky</surname> <given-names>J</given-names></name> <name><surname>Decaunes</surname> <given-names>P</given-names></name> <name><surname>Est&#x000E8;ve</surname> <given-names>D</given-names></name> <name><surname>Marques</surname> <given-names>M-A</given-names></name> <name><surname>Sengen&#x000E8;s</surname> <given-names>C</given-names></name> <etal/></person-group>. <article-title>Adipose tissue endothelial cells from obese human subjects: differences among depots in angiogenic, metabolic, and inflammatory gene expression and cellular senescence</article-title>. <source>Diabetes.</source> (<year>2010</year>) <volume>59</volume>:<fpage>2755</fpage>&#x02013;<lpage>63</lpage>. <pub-id pub-id-type="doi">10.2337/db10-0398</pub-id><pub-id pub-id-type="pmid">20713685</pub-id></citation></ref>
<ref id="B60">
<label>60.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Korbecki</surname> <given-names>J</given-names></name> <name><surname>Bajdak-Rusinek</surname> <given-names>K</given-names></name></person-group>. <article-title>The effect of palmitic acid on inflammatory response in macrophages: an overview of molecular mechanisms</article-title>. <source>Inflamm Res.</source> (<year>2019</year>) <volume>68</volume>:<fpage>915</fpage>&#x02013;<lpage>32</lpage>. <pub-id pub-id-type="doi">10.1007/s00011-019-01273-5</pub-id><pub-id pub-id-type="pmid">31363792</pub-id></citation></ref>
<ref id="B61">
<label>61.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Mao</surname> <given-names>Y</given-names></name> <name><surname>Luo</surname> <given-names>W</given-names></name> <name><surname>Zhang</surname> <given-names>L</given-names></name> <name><surname>Wu</surname> <given-names>W</given-names></name> <name><surname>Yuan</surname> <given-names>L</given-names></name> <name><surname>Xu</surname> <given-names>H</given-names></name> <etal/></person-group>. <article-title>STING-IRF3 triggers endothelial inflammation in response to free fatty acid-induced mitochondrial damage in diet-induced obesity</article-title>. <source>Arterioscler Thromb Vasc Biol.</source> (<year>2017</year>) <volume>37</volume>:<fpage>920</fpage>&#x02013;<lpage>9</lpage>. <pub-id pub-id-type="doi">10.1161/ATVBAHA.117.309017</pub-id><pub-id pub-id-type="pmid">29563119</pub-id></citation></ref>
<ref id="B62">
<label>62.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gong</surname> <given-names>Y</given-names></name> <name><surname>Li</surname> <given-names>G</given-names></name> <name><surname>Tao</surname> <given-names>J</given-names></name> <name><surname>Wu</surname> <given-names>NN</given-names></name> <name><surname>Kandadi</surname> <given-names>MR</given-names></name> <name><surname>Bi</surname> <given-names>Y</given-names></name> <etal/></person-group>. <article-title>Double knockout of Akt2 and AMPK accentuates high fat diet-induced cardiac anomalies through a cGAS-STING-mediated mechanism</article-title>. <source>Biochim Biophys Acta Mol Basis Dis.</source> (<year>2020</year>) <volume>1866</volume>:<fpage>165855</fpage>. <pub-id pub-id-type="doi">10.1016/j.bbadis.2020.165855</pub-id><pub-id pub-id-type="pmid">32512189</pub-id></citation></ref>
<ref id="B63">
<label>63.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Russell</surname> <given-names>RC</given-names></name> <name><surname>Tian</surname> <given-names>Y</given-names></name> <name><surname>Yuan</surname> <given-names>H</given-names></name> <name><surname>Park</surname> <given-names>HW</given-names></name> <name><surname>Chang</surname> <given-names>Y-Y</given-names></name> <name><surname>Kim</surname> <given-names>J</given-names></name> <etal/></person-group>. <article-title>ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase</article-title>. <source>Nat Cell Biol.</source> (<year>2013</year>) <volume>15</volume>:<fpage>741</fpage>&#x02013;<lpage>50</lpage>. <pub-id pub-id-type="doi">10.1038/ncb2757</pub-id><pub-id pub-id-type="pmid">23685627</pub-id></citation></ref>
<ref id="B64">
<label>64.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Franceschi</surname> <given-names>C</given-names></name> <name><surname>Garagnani</surname> <given-names>P</given-names></name> <name><surname>Parini</surname> <given-names>P</given-names></name> <name><surname>Giuliani</surname> <given-names>C</given-names></name> <name><surname>Santoro</surname> <given-names>A</given-names></name></person-group>. <article-title>Inflammaging: a new immune-metabolic viewpoint for age-related diseases</article-title>. <source>Nat Rev Endocrinol.</source> (<year>2018</year>) <volume>14</volume>:<fpage>576</fpage>&#x02013;<lpage>90</lpage>. <pub-id pub-id-type="doi">10.1038/s41574-018-0059-4</pub-id><pub-id pub-id-type="pmid">30046148</pub-id></citation></ref>
<ref id="B65">
<label>65.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Quan</surname> <given-names>Y</given-names></name> <name><surname>Xin</surname> <given-names>Y</given-names></name> <name><surname>Tian</surname> <given-names>G</given-names></name> <name><surname>Zhou</surname> <given-names>J</given-names></name> <name><surname>Liu</surname> <given-names>X</given-names></name></person-group>. <article-title>Mitochondrial ROS-Modulated mtDNA: a potential target for cardiac aging</article-title>. <source>Oxid Med Cell Longev.</source> (<year>2020</year>) <volume>2020</volume>:<fpage>9423593</fpage>. <pub-id pub-id-type="doi">10.1155/2020/9423593</pub-id><pub-id pub-id-type="pmid">32308810</pub-id></citation></ref>
<ref id="B66">
<label>66.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Padilla-S&#x000E1;nchez</surname> <given-names>SD</given-names></name> <name><surname>Navarrete</surname> <given-names>D</given-names></name> <name><surname>Caicedo</surname> <given-names>A</given-names></name> <name><surname>Teran</surname> <given-names>E</given-names></name></person-group>. <article-title>Circulating cell-free mitochondrial DNA levels correlate with body mass index and age</article-title>. <source>Biochim Biophys Acta Mol Basis Dis.</source> (<year>2020</year>) <volume>1866</volume>:<fpage>165963</fpage>. <pub-id pub-id-type="doi">10.1016/j.bbadis.2020.165963</pub-id><pub-id pub-id-type="pmid">32919035</pub-id></citation></ref>
<ref id="B67">
<label>67.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Pinti</surname> <given-names>M</given-names></name> <name><surname>Cevenini</surname> <given-names>E</given-names></name> <name><surname>Nasi</surname> <given-names>M</given-names></name> <name><surname>de Biasi</surname> <given-names>S</given-names></name> <name><surname>Salvioli</surname> <given-names>S</given-names></name> <name><surname>Monti</surname> <given-names>D</given-names></name> <etal/></person-group>. <article-title>Circulating mitochondrial DNA increases with age and is a familiar trait: Implications for &#x0201C;inflamm-aging&#x0201D;</article-title>. <source>Eur J Immunol.</source> (<year>2014</year>) <volume>44</volume>:<fpage>1552</fpage>&#x02013;<lpage>62</lpage>. <pub-id pub-id-type="doi">10.1002/eji.201343921</pub-id><pub-id pub-id-type="pmid">24470107</pub-id></citation></ref>
<ref id="B68">
<label>68.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ponikowski</surname> <given-names>P</given-names></name> <name><surname>Voors</surname> <given-names>AA</given-names></name> <name><surname>Anker</surname> <given-names>SD</given-names></name> <name><surname>Bueno</surname> <given-names>H</given-names></name> <name><surname>Cleland</surname> <given-names>JGF</given-names></name> <name><surname>Coats</surname> <given-names>AJS</given-names></name> <etal/></person-group>. <article-title>2016 ESC Guidelines for the diagnosis treatment of acute chronic heart failure: The Task Force for the diagnosis treatment of acute chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC</article-title>. <source>Eur Heart J</source>. (<year>2016</year>) <volume>37</volume>:<fpage>2129</fpage>&#x02013;<lpage>200</lpage>. <pub-id pub-id-type="doi">10.1093/eurheartj/ehw128</pub-id><pub-id pub-id-type="pmid">27207191</pub-id></citation></ref>
<ref id="B69">
<label>69.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Gonzalo</surname> <given-names>S</given-names></name> <name><surname>Coll-Bonfill</surname> <given-names>N</given-names></name></person-group>. <article-title>Genomic instability and innate immune responses to self-DNA in progeria</article-title>. <source>Geroscience.</source> (<year>2019</year>) <volume>41</volume>:<fpage>255</fpage>&#x02013;<lpage>66</lpage>. <pub-id pub-id-type="doi">10.1007/s11357-019-00082-2</pub-id><pub-id pub-id-type="pmid">31280482</pub-id></citation></ref>
<ref id="B70">
<label>70.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Graziano</surname> <given-names>S</given-names></name> <name><surname>Kreienkamp</surname> <given-names>R</given-names></name> <name><surname>Coll-Bonfill</surname> <given-names>N</given-names></name> <name><surname>Gonzalo</surname> <given-names>S</given-names></name></person-group>. <article-title>Causes and consequences of genomic instability in laminopathies: replication stress and interferon response</article-title>. <source>Nucleus.</source> (<year>2018</year>) <volume>9</volume>:<fpage>258</fpage>&#x02013;<lpage>75</lpage>. <pub-id pub-id-type="doi">10.1080/19491034.2018.1454168</pub-id><pub-id pub-id-type="pmid">29637811</pub-id></citation></ref>
<ref id="B71">
<label>71.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Kreienkamp</surname> <given-names>R</given-names></name> <name><surname>Graziano</surname> <given-names>S</given-names></name> <name><surname>Coll-Bonfill</surname> <given-names>N</given-names></name> <name><surname>Bedia-Diaz</surname> <given-names>G</given-names></name> <name><surname>Cybulla</surname> <given-names>E</given-names></name> <name><surname>Vindigni</surname> <given-names>A</given-names></name> <etal/></person-group>. <article-title>A cell-intrinsic interferon-like response links replication stress to cellular aging caused by progerin</article-title>. <source>Cell Rep.</source> (<year>2018</year>) <volume>22</volume>:<fpage>2006</fpage>&#x02013;<lpage>15</lpage>. <pub-id pub-id-type="doi">10.1016/j.celrep.2018.01.090</pub-id><pub-id pub-id-type="pmid">29466729</pub-id></citation></ref>
<ref id="B72">
<label>72.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Hamann</surname> <given-names>L</given-names></name> <name><surname>Ruiz-Moreno</surname> <given-names>JS</given-names></name> <name><surname>Szwed</surname> <given-names>M</given-names></name> <name><surname>Mossakowska</surname> <given-names>M</given-names></name> <name><surname>Lundvall</surname> <given-names>L</given-names></name> <name><surname>Schumann</surname> <given-names>RR</given-names></name> <etal/></person-group>. <article-title>STING SNP R293Q is associated with a decreased risk of aging-related diseases</article-title>. <source>Gerontology.</source> (<year>2019</year>) <volume>65</volume>:<fpage>145</fpage>&#x02013;<lpage>54</lpage>. <pub-id pub-id-type="doi">10.1159/000492972</pub-id><pub-id pub-id-type="pmid">30368497</pub-id></citation></ref>
<ref id="B73">
<label>73.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Hamann</surname> <given-names>L</given-names></name> <name><surname>Szwed</surname> <given-names>M</given-names></name> <name><surname>Mossakowska</surname> <given-names>M</given-names></name> <name><surname>Chudek</surname> <given-names>J</given-names></name> <name><surname>Puzianowska-Kuznicka</surname> <given-names>M</given-names></name></person-group>. <article-title>First evidence for STING SNP R293Q being protective regarding obesity-associated cardiovascular disease in age-advanced subjects - a cohort study</article-title>. <source>Immun Ageing.</source> (<year>2020</year>) <volume>17</volume>:<fpage>7</fpage>. <pub-id pub-id-type="doi">10.1186/s12979-020-00176-y</pub-id><pub-id pub-id-type="pmid">32190093</pub-id></citation></ref>
<ref id="B74">
<label>74.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Zhang</surname> <given-names>Y</given-names></name> <name><surname>Chen</surname> <given-names>W</given-names></name> <name><surname>Wang</surname> <given-names>Y</given-names></name></person-group>. <article-title>STING is an essential regulator of heart inflammation and fibrosis in mice with pathological cardiac hypertrophy <italic>via</italic> endoplasmic reticulum (ER) stress</article-title>. <source>Biomed Pharmacother.</source> (<year>2020</year>) <volume>125</volume>:<fpage>110022</fpage>. <pub-id pub-id-type="doi">10.1016/j.biopha.2020.110022</pub-id><pub-id pub-id-type="pmid">32106379</pub-id></citation></ref>
<ref id="B75">
<label>75.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Hu</surname> <given-names>D</given-names></name> <name><surname>Cui</surname> <given-names>Y-X</given-names></name> <name><surname>Wu</surname> <given-names>M-Y</given-names></name> <name><surname>Li</surname> <given-names>L</given-names></name> <name><surname>Su</surname> <given-names>L-N</given-names></name> <name><surname>Lian</surname> <given-names>Z</given-names></name> <etal/></person-group>. <article-title>Cytosolic DNA sensor cGAS plays an essential pathogenetic role in pressure overload-induced heart failure</article-title>. <source>Am J Physiol Heart Circ Physiol.</source> (<year>2020</year>) <volume>318</volume>:<fpage>H1525</fpage>&#x02013;<lpage>37</lpage>. <pub-id pub-id-type="doi">10.1152/ajpheart.00097.2020</pub-id><pub-id pub-id-type="pmid">32383996</pub-id></citation></ref>
<ref id="B76">
<label>76.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Cao</surname> <given-names>DJ</given-names></name> <name><surname>Schiattarella</surname> <given-names>GG</given-names></name> <name><surname>Villalobos</surname> <given-names>E</given-names></name> <name><surname>Jiang</surname> <given-names>N</given-names></name> <name><surname>May</surname> <given-names>HI</given-names></name> <name><surname>Li</surname> <given-names>T</given-names></name> <etal/></person-group>. <article-title>Cytosolic DNA sensing promotes macrophage transformation and governs myocardial ischemic injury</article-title>. <source>Circulation.</source> (<year>2018</year>) <volume>137</volume>:<fpage>2613</fpage>&#x02013;<lpage>34</lpage>. <pub-id pub-id-type="doi">10.1161/CIRCULATIONAHA.117.031046</pub-id><pub-id pub-id-type="pmid">29437120</pub-id></citation></ref>
<ref id="B77">
<label>77.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>King</surname> <given-names>KR</given-names></name> <name><surname>Aguirre</surname> <given-names>AD</given-names></name> <name><surname>Ye</surname> <given-names>Y-X</given-names></name> <name><surname>Sun</surname> <given-names>Y</given-names></name> <name><surname>Roh</surname> <given-names>JD Ng</given-names></name> <etal/></person-group>. <article-title>IRF3 and type I interferons fuel a fatal response to myocardial infarction</article-title>. <source>Nat Med.</source> (<year>2017</year>) <volume>23</volume>:<fpage>1481</fpage>&#x02013;<lpage>7</lpage>. <pub-id pub-id-type="doi">10.1038/nm.4428</pub-id><pub-id pub-id-type="pmid">29106401</pub-id></citation></ref>
<ref id="B78">
<label>78.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Li</surname> <given-names>Q</given-names></name> <name><surname>Cao</surname> <given-names>Y</given-names></name> <name><surname>Dang</surname> <given-names>C</given-names></name> <name><surname>Han</surname> <given-names>B</given-names></name> <name><surname>Han</surname> <given-names>R</given-names></name> <name><surname>Ma</surname> <given-names>H</given-names></name> <etal/></person-group>. <article-title>Inhibition of double-strand DNA-sensing cGAS ameliorates brain injury after ischemic stroke</article-title>. <source>EMBO Mol Med.</source> (<year>2020</year>) <volume>12</volume>:<fpage>e11002</fpage>. <pub-id pub-id-type="doi">10.15252/emmm.201911002</pub-id><pub-id pub-id-type="pmid">32239625</pub-id></citation></ref>
<ref id="B79">
<label>79.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Li</surname> <given-names>N</given-names></name> <name><surname>Zhou</surname> <given-names>H</given-names></name> <name><surname>Wu</surname> <given-names>H</given-names></name> <name><surname>Wu</surname> <given-names>Q</given-names></name> <name><surname>Duan</surname> <given-names>M</given-names></name> <name><surname>Deng</surname> <given-names>W</given-names></name> <etal/></person-group>. <article-title>STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3</article-title>. <source>Redox Biol.</source> (<year>2019</year>) <volume>24</volume>:<fpage>101215</fpage>. <pub-id pub-id-type="doi">10.1016/j.redox.2019.101215</pub-id><pub-id pub-id-type="pmid">31121492</pub-id></citation></ref>
<ref id="B80">
<label>80.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Xu</surname> <given-names>Q</given-names></name> <name><surname>Xiong</surname> <given-names>H</given-names></name> <name><surname>Zhu</surname> <given-names>W</given-names></name> <name><surname>Liu</surname> <given-names>Y</given-names></name> <name><surname>Du</surname> <given-names>Y</given-names></name></person-group>. <article-title>Small molecule inhibition of cyclic GMP-AMP synthase ameliorates sepsis-induced cardiac dysfunction in mice</article-title>. <source>Life Sci</source>. (<year>2020</year>) <volume>260</volume>:<fpage>118315</fpage>. <pub-id pub-id-type="doi">10.1016/j.lfs.2020.118315</pub-id><pub-id pub-id-type="pmid">32835697</pub-id></citation></ref>
<ref id="B81">
<label>81.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname> <given-names>X</given-names></name> <name><surname>Yang</surname> <given-names>B</given-names></name> <name><surname>Cao</surname> <given-names>H-L</given-names></name> <name><surname>Wang</surname> <given-names>R-Y</given-names></name> <name><surname>Lu</surname> <given-names>Z-Y</given-names></name> <name><surname>Chi</surname> <given-names>R-F</given-names></name> <etal/></person-group>. <article-title>Selenium supplementation protects against lipopolysaccharide-induced heart injury <italic>via</italic> STING pathway in mice</article-title>. <source>Biol Trace Elem Res.</source> (<year>2020</year>) <volume>199</volume>:<fpage>1885</fpage>&#x02013;<lpage>92</lpage>. <pub-id pub-id-type="doi">10.1007/s12011-020-02295-5</pub-id><pub-id pub-id-type="pmid">32737811</pub-id></citation></ref>
<ref id="B82">
<label>82.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Choudhuri</surname> <given-names>S</given-names></name> <name><surname>Garg</surname> <given-names>NJ</given-names></name></person-group>. <article-title>PARP1-cGAS-NF-kappa B pathway of proinflammatory macrophage activation by extracellular vesicles released during Trypanosoma cruzi infection and chagas disease</article-title>. <source>PLoS Pathogens.</source> (<year>2020</year>) <volume>16</volume>:<fpage>e1008474</fpage>. <pub-id pub-id-type="doi">10.1371/journal.ppat.1008474</pub-id><pub-id pub-id-type="pmid">32315358</pub-id></citation></ref>
<ref id="B83">
<label>83.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Berthelot</surname> <given-names>J-M</given-names></name> <name><surname>Liot&#x000E9;</surname> <given-names>F</given-names></name> <name><surname>Maugars</surname> <given-names>Y</given-names></name> <name><surname>Sibilia</surname> <given-names>J</given-names></name></person-group>. <article-title>Lymphocyte changes in severe COVID-19: delayed over-activation of STING?</article-title> <source>Front Immunol.</source> (<year>2020</year>) <volume>11</volume>:<fpage>607069</fpage>. <pub-id pub-id-type="doi">10.3389/fimmu.2020.607069</pub-id><pub-id pub-id-type="pmid">33335532</pub-id></citation></ref>
<ref id="B84">
<label>84.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Basso</surname> <given-names>C</given-names></name> <name><surname>Leone</surname> <given-names>O</given-names></name> <name><surname>Rizzo</surname> <given-names>S</given-names></name> <name><surname>Gaspari</surname> <given-names>M de</given-names></name> <name><surname>van</surname> <given-names>der Wal AC</given-names></name> <name><surname>Aubry</surname> <given-names>M-C</given-names></name> <etal/></person-group>. <article-title>Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study</article-title>. <source>Eur Heart J.</source> (<year>2020</year>) <volume>41</volume>:<fpage>3827</fpage>&#x02013;<lpage>35</lpage>. <pub-id pub-id-type="doi">10.1093/eurheartj/ehaa664</pub-id><pub-id pub-id-type="pmid">32968776</pub-id></citation></ref>
<ref id="B85">
<label>85.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Durante</surname> <given-names>M</given-names></name> <name><surname>Formenti</surname> <given-names>SC</given-names></name></person-group>. <article-title>Radiation-induced chromosomal aberrations and immunotherapy: micronuclei, cytosolic DNA, and interferon-production pathway</article-title>. <source>Front Oncol.</source> (<year>2018</year>) <volume>8</volume>:<fpage>192</fpage>. <pub-id pub-id-type="doi">10.3389/fonc.2018.00192</pub-id><pub-id pub-id-type="pmid">29911071</pub-id></citation></ref>
<ref id="B86">
<label>86.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Philipp</surname> <given-names>J</given-names></name> <name><surname>Le Gleut</surname> <given-names>R</given-names></name> <name><surname>Toerne</surname> <given-names>CV</given-names></name> <name><surname>Subedi</surname> <given-names>P</given-names></name> <name><surname>Azimzadeh</surname> <given-names>O</given-names></name> <name><surname>Atkinson</surname> <given-names>MJ</given-names></name> <etal/></person-group>. <article-title>Radiation response of human cardiac endothelial cells reveals a central role of the cGAS-STING Pathway in the development of inflammation</article-title>. <source>Proteomes.</source> (<year>2020</year>) <volume>8</volume>:<fpage>30</fpage>. <pub-id pub-id-type="doi">10.3390/proteomes8040030</pub-id><pub-id pub-id-type="pmid">33114474</pub-id></citation></ref>
<ref id="B87">
<label>87.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Aznar</surname> <given-names>MC</given-names></name> <name><surname>Korreman</surname> <given-names>S-S</given-names></name> <name><surname>Pedersen</surname> <given-names>AN</given-names></name> <name><surname>Persson</surname> <given-names>GF</given-names></name> <name><surname>Josipovic</surname> <given-names>M</given-names></name> <name><surname>Specht</surname> <given-names>L</given-names></name></person-group>. <article-title>Evaluation of dose to cardiac structures during breast irradiation</article-title>. <source>Br J Radiol.</source> (<year>2011</year>) <volume>84</volume>:<fpage>743</fpage>&#x02013;<lpage>6</lpage>. <pub-id pub-id-type="doi">10.1259/bjr/12497075</pub-id><pub-id pub-id-type="pmid">21159806</pub-id></citation></ref>
<ref id="B88">
<label>88.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Vanpouille-Box</surname> <given-names>C</given-names></name> <name><surname>Hoffmann</surname> <given-names>JA</given-names></name> <name><surname>Galluzzi</surname> <given-names>L</given-names></name></person-group>. <article-title>Pharmacological modulation of nucleic acid sensors - therapeutic potential and persisting obstacles</article-title>. <source>Nat Rev Drug Discov.</source> (<year>2019</year>) <volume>18</volume>:<fpage>845</fpage>&#x02013;<lpage>67</lpage>. <pub-id pub-id-type="doi">10.1038/s41573-019-0043-2</pub-id><pub-id pub-id-type="pmid">31554927</pub-id></citation></ref>
<ref id="B89">
<label>89.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>An</surname> <given-names>J</given-names></name> <name><surname>Woodward</surname> <given-names>JJ</given-names></name> <name><surname>Lai</surname> <given-names>W</given-names></name> <name><surname>Minie</surname> <given-names>M</given-names></name> <name><surname>Sun</surname> <given-names>X</given-names></name> <name><surname>Tanaka</surname> <given-names>L</given-names></name> <etal/></person-group>. <article-title>Inhibition of cyclic GMP-AMP synthase using a novel antimalarial drug derivative in Trex1-deficient mice</article-title>. <source>Arthritis Rheumatol.</source> (<year>2018</year>) <volume>70</volume>:<fpage>1807</fpage>&#x02013;<lpage>19</lpage>. <pub-id pub-id-type="doi">10.1002/art.40559</pub-id><pub-id pub-id-type="pmid">29781188</pub-id></citation></ref>
<ref id="B90">
<label>90.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Lama</surname> <given-names>L</given-names></name> <name><surname>Adura</surname> <given-names>C</given-names></name> <name><surname>Xie</surname> <given-names>W</given-names></name> <name><surname>Tomita</surname> <given-names>D</given-names></name> <name><surname>Kamei</surname> <given-names>T</given-names></name> <name><surname>Kuryavyi</surname> <given-names>V</given-names></name> <etal/></person-group>. <article-title>Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression</article-title>. <source>Nat Commun.</source> (<year>2019</year>) <volume>10</volume>:<fpage>1</fpage>&#x02013;<lpage>14</lpage>. <pub-id pub-id-type="doi">10.1038/s41467-019-08620-4</pub-id><pub-id pub-id-type="pmid">31113940</pub-id></citation></ref>
<ref id="B91">
<label>91.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Sheridan</surname> <given-names>C</given-names></name></person-group>. <article-title>Drug developers switch gears to inhibit STING</article-title>. <source>Nat Biotechnol.</source> (<year>2019</year>) <volume>37</volume>:<fpage>199</fpage>&#x02013;<lpage>201</lpage>. <pub-id pub-id-type="doi">10.1038/s41587-019-0060-z</pub-id></citation></ref>
<ref id="B92">
<label>92.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Li</surname> <given-names>S</given-names></name> <name><surname>Hong</surname> <given-names>Z</given-names></name> <name><surname>Wang</surname> <given-names>Z</given-names></name> <name><surname>Li</surname> <given-names>F</given-names></name> <name><surname>Mei</surname> <given-names>J</given-names></name> <name><surname>Huang</surname> <given-names>L</given-names></name> <etal/></person-group>. <article-title>The cyclopeptide astin c specifically inhibits the innate immune CDN sensor STING</article-title>. <source>Cell Rep.</source> (<year>2018</year>) <volume>25</volume>:<fpage>3405</fpage>&#x02013;<lpage>3421.e7</lpage>. <pub-id pub-id-type="doi">10.1016/j.celrep.2018.11.097</pub-id><pub-id pub-id-type="pmid">30566866</pub-id></citation></ref>
<ref id="B93">
<label>93.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Haag</surname> <given-names>SM</given-names></name> <name><surname>Gulen</surname> <given-names>MF</given-names></name> <name><surname>Reymond</surname> <given-names>L</given-names></name> <name><surname>Gibelin</surname> <given-names>A</given-names></name> <name><surname>Abrami</surname> <given-names>L</given-names></name> <name><surname>Decout</surname> <given-names>A</given-names></name> <etal/></person-group>. <article-title>Targeting STING with covalent small-molecule inhibitors</article-title>. <source>Nature.</source> (<year>2018</year>) <volume>559</volume>:<fpage>269</fpage>&#x02013;<lpage>73</lpage>. <pub-id pub-id-type="doi">10.1038/s41586-018-0287-8</pub-id><pub-id pub-id-type="pmid">29973723</pub-id></citation></ref>
<ref id="B94">
<label>94.</label>
<citation citation-type="journal"><person-group person-group-type="author"><name><surname>Ge</surname> <given-names>W</given-names></name> <name><surname>Hu</surname> <given-names>Q</given-names></name> <name><surname>Fang</surname> <given-names>X</given-names></name> <name><surname>Liu</surname> <given-names>J</given-names></name> <name><surname>Xu</surname> <given-names>J</given-names></name> <name><surname>Hu</surname> <given-names>J</given-names></name> <etal/></person-group>. <article-title>LDK378 improves micro- and macro-circulation <italic>via</italic> alleviating STING-mediated inflammatory injury in a sepsis rat model induced by cecal ligation and puncture</article-title>. <source>J Inflamm.</source> (<year>2019</year>) <volume>16</volume>:<fpage>3</fpage>. <pub-id pub-id-type="doi">10.1186/s12950-019-0208-0</pub-id><pub-id pub-id-type="pmid">30820191</pub-id></citation></ref>
</ref-list>
<fn-group>
<fn fn-type="financial-disclosure"><p><bold>Funding.</bold> PR is supported by the Austrian Science Fund, ERA-CVD (AIR-MI, I 4168-B), and the Austrian Society of Cardiology.</p>
</fn>
</fn-group>
</back>
</article>
