Abstract
The most severe clinical manifestations of the horrifying COVID-19 disease, that claimed millions of lives during the pandemic time, were Acute respiratory distress syndrome (ARDS), Coagulopathies, septic shock leading eventually to death. ARDS was a consequence of Cytokine storm. The viral SARS-COV2infection lead to avalanche of cytokines and eicosanoids causing “cytokine storm” and “eicosanoid storm.” Cytokine storm is one of the macrophage-derived inflammatory responses triggered by binding of virus particles to ACE2 receptors of alveolar macrophages, arise mainly due to over production of various pro-inflammatory mediators like cytokines, e.g., interleukin (IL)-1, IL-2, and tumor necrosis factor (TNF)- α, causing pulmonary edema, acute respiratory distress, and multi-organ failure. Cytokine storm was regarded as the predictor of severity of the disease and was deemed one of the causes of the high mortality rates due to the COVID-19. The basis of cytokine storm is imbalanced switching between an inflammation increasing - pro-inflammatory (M1) and an inflammation regulating-anti-inflammatory (M2) forms of alveolar macrophages which further deteriorates if opportunistic secondary bacterial infections prevail in the lungs. Lack of sufficient knowledge regarding the virus and its influence on co-morbidities, clinical treatment of the diseases included exorbitant use of antibiotics to mitigate secondary bacterial infections, which led to the unwarranted development of multidrug resistance (MDR) among the population across the globe. Antimicrobial resistance (AMR) needs to be addressed from various perspectives as it may deprive future generations of the basic health immunity. Specialized pro-resolving mediators (SPMs) are generated from the stereoselective enzymatic conversions of essential fatty acids that serve as immune resolvents in controlling acute inflammatory responses. SPMs facilitate the clearance of injured tissue and cell debris, the removal of pathogens, and augment the concentration of anti-inflammatory lipid mediators. The SPMs, e.g., lipoxins, protectins, and resolvins have been implicated in exerting inhibitory influence on with cytokine storm. Experimental evidence suggests that SPMS lower antibiotic requirement. Therefore, in this review potential roles of SPMs in enhancing macrophage polarization, triggering immunological functions, hastening inflammation resolution, subsiding cytokine storm and decreasing antibiotic requirement that can reduce AMR load are discussed.
Introduction
At the time of publication of this article a total of 113 million individuals have been clinically affected by the current pandemic. Of these, approximately 89 million have recovered, 21 million still have not and more than 2 million lives have been lost to the disease. The causative organism for the coronavirus disease 2019 (COVID-19) is the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which is an enveloped, single-stranded, positive-sense RNA virus, that belongs to the group of Beta coronaviruses 2b lineage of the family coronaviridae, and the order Nidovirales (; ; ). It closely resembles SARS-CoV as 79.5% of its genomic sequence is identical to the latter (Shin et al., 2020; Zhou F et al., 2020; Zhou P et al., 2020). SARS-CoV-2 has spherical morphology, with spike-like glycoproteins (S proteins) protruding from its surface. Their S1 and S2 subdomains are crucial in host cell receptor binding and fusion with cell membrane. The former shows more variation across the receptor-binding domain (RBD), whereas the S2 subdomain is conserved, comprising of the fusion machinery necessary for the virus to reach the host cell (Shin et al., 2020).
Co-infections and superinfections that occur in conjunction with viral respiratory infections can significantly increase the mortality rate of patients, as pointed out in laboratory, clinical, and epidemiological studies (; ). Bacterial co-infections were specifically recorded as being able to alter the mortality rate in viral infections, of which influenza-related bacterial infections are a prime example (Smith and McCullers, 2014; ; ; ). Streptococcus pyogenes, Neisseria meningitidis, Moraxella catarrhalis, Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus are all capable of causing influenza-related infections (; ; Smith and McCullers, 2014; ; ; Su et al., 2019). Antibiotics are being used in abundance despite COVID-19 being caused by a virus to treat or prevent secondary infections (Zhou, F et al., 2020; ). This is cause for concern as there is a lack of new antibiotics to deal with drug-resistant bacterial infections, which arose due to the overuse of antibiotics in the first place. (). Additionally, the use of sanitizers and disinfectants, that has increased severalfold as measures to prevent infection spread increase the risk of antimicrobial resistance ().
COVID-19 progression involves pulmonary hyper-inflammation and release of pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-1, IL-8, and MCP-1), as part of “cytokine storms” (). Cell death and the resulting cell debris accumulation triggers inflammasomes, which bring about a surge of pro-inflammatory bioactive lipid mediators like prostaglandins and leukotrienes (“eicosanoid storm”) resulting in local inflammation (von Moltke et al., 2012). Management of these local and systematic responses are as crucial an antiviral therapy. Eicosanoids are endogenous lipid autacoid mediators capable of inducing inflammation, while endogenous pro-resolution lipids are anti-inflammatory agents that can terminate the inflammatory response by promoting the removal of cellular debris (). Specialized pro-resolving mediators (SPMs) are bioactive lipid autacoids that can stimulate phagocytosis of cellular debris by macrophages as well as counter the release of pro-inflammatory cytokines/chemokines, thereby bringing about endogenous resolution of inflammatory response. Discovery of SPMs such as resolvins, lipoxins, and protectins has given traction to the idea that inflammation resolution is an active biochemical process (Serhan, 2014).
Alveolar macrophages may be integral to COVID-19 disease progression and disease-induced deaths. Infection of lungs by SARS-CoV-2 virus followed by failure to rapidly remove the virus leads to severe inflammatory response, tissue damage and fibrosis. Prolonged overactivation of macrophages and increased release of pro-inflammatory cytokines result in clinical manifestations that are markedly identical to those of macrophage activation syndrome (MAS). This being the case, identifying methods to regulate macrophage response in cases of severe COVID-19 is key to recovery (Tang L et al., 2020). In this review, we discuss the role of Specialized Pro-resolving lipid Mediators (SPMs) in driving the macrophages immuno-functions and thus regulating the macrophage-induced inflammation. Moreover, we discuss the clinical potentials of SPMs in COVID-19 treatment.
Antimicrobial resistance in the COVID-19 ERA
Antimicrobial resistance (AMR) emerged as a notable issue quite a while before the start of the COVID-19 pandemic. With the influx of novel antibiotics at a decline since the 1980s, instances of reported cases of infections by drug-resistant organisms have soared (). COVID-19, being caused by the virus SARS-CoV-2, one might assume that antibiotics are of little to no use. However, there are a few factors that necessitate the use of antimicrobials. One of these reasons is that symptoms of COVID-19 closely resemble those of bacterial pneumonia and as such, antibiotics are prescribed immediately in severe cases prior to confirmation via diagnostic testing. Another reason is secondary infections associated with COVID-19, where antimicrobial use is required to kill invading bacteria and fungi (). Besides prescription, individuals also consumed pharmaceuticals compounds whose efficacy was unproven under the influence of social media discourse (). These situations led to the use and abuse of antimicrobials during the pandemic, and it is precisely their use that leads to antimicrobial resistance. The CDC (Centers for Disease Control and Prevention, United States of America) released a 2022 special report on antimicrobial resistance, highlighting the changes in trends that occurred during the response to COVID-19. The report considered 18 antimicrobial resistance threats, and for these data was unavailable for 9, while all the rest showed significant increase in infection rates (). Overall, cases of antimicrobial resistance have increased in the COVID-19 era.
Choice of antibiotics for COVID-19 patients
The CDC reported that during the pandemic response, 80% of patients admitted to US hospitals were given antibiotic treatment, either due to their condition being confused with bacterial pneumonia or because of secondary infections. The two most common antibiotics prescribed were azithromycin and ceftriaxone (). Clinicians were concerned with two priorities while prescribing antibiotics—one was prescribing an antibiotic with a broad enough spectrum to be effective against the organism, while the other involved not using last resort antibiotics and preventing wastage (). Secondary infections with viral diseases are usually due to Staphylococcus aureus, Streptococcus pneumoniae, Neisseria meningitides, Haemophilus influenzae, Klebsiella pneumoniae, and members of the genus Proteus, Enterobacter, and Citrobacter species. These are present in the hospital setting, and their spread is nosocomial (). Drug-resistant organisms, such as multidrug-resistant Escherichia coli, Enterococcus, Chlamydia pneumoniae, Klebsiella pneumonia, Pseudomonas aeruginosa, Mycoplasma pneumonia, and extended-spectrum beta-lactamase are associated with SARS-CoV-2 infections (). It was reported that the following antibiotics were used to treat COVID-19: cephalosporins, quinolones, carbapenems, tigecycline against methicillin-resistant Staphylococcus aureus, linezolid, antifungal drugs (). However, the usage of several other antibacterials was noted such as moxifloxacin, ceftriaxone, and azithromycin (Wang et al., 2020). The best way to prevent prescription and eventual abuse of antibiotics remain prevention of infections from occurring in the first place.
Antimicrobial resistance pattern in COVID-19
Antimicrobial resistance emerges in response to changes—man-made or natural—that might occur in their environment. Generally, mutation of genes and horizontal transfer of existing resistance genes can result in resistance to antimicrobial agents (). Going into the pandemic, warnings were issued that prolonged and inappropriate use of antimicrobials will exacerbate the problem of AMR, such that their spike in use will result in more deaths in the future (). The general mechanisms of antimicrobial resistance are antibiotic destruction or modification through enzymatic means, alteration to target of antibiotic action, changes to membrane permeability and pumping out antimicrobial compounds via efflux pumps (). The major change introduced during the pandemic was the frequency with which biocides and pharmaceutical compounds were brought in contact with microbes in the body and the environment. These involve alcohol-based hand sanitizers, surfactants, phenols, quaternary ammonium compounds, hydrogen peroxide and others (). Mutagenesis-induced tolerance of alcohol had been reported in bacteria even before the start of the pandemic (). Frequent use of antimicrobial agents places stress on organisms, resulting in selection of colonies capable of withstanding the effects of these compounds. Prolonged exposure can thus result in these compounds becoming ineffective (; ).
SPMs in infection
Specialized pro resolving mediators (SPMs) are endogenous lipid mediators, produced from innate immune cells, formed via stereoselective enzymatic conversion of essential fatty acids like arachidonic acid, eicosapentaenoic acid (EPA, C20:5n-3), n-3 docosapentanoic acid and docosahexaenoic acid (DHA, C22:6–3) (). The different subgroups of SPMs identified are: resolvins (Rvs), protectins, maresins, and lipoxins. SPMS, are antimicrobial in nature, clear the debris of killed pathogens by immunocytes, facilitate the clearance of injured tissue and cell debris. They inhibit PMN infiltration and recruitment, enhance macrophage phagocytosis, and stimulate efferocytosis by activating macrophage polarization from M1 to M2 (; ). Furthermore, SPMs decrease the release of pro-inflammatory chemical mediators, whilst increase the anti-inflammatory mediators such as IL-10, thereby reduces both cytokine and eicosanoid storms (Schif-Zuck et al., 2011; Titos et al., 2016; ). Finally, they exhibit anti-nociceptive effects by reducing inflammatory pain, stimulate tissue regeneration, and enhance wound healing (; Serhan et al., 2012; Regidor et al., 2020). SPMs serve as immune resolvents in controlling acute inflammatory responses and augment the concentration of anti-inflammatory lipid mediators. Evidence from several studies, signify the role of SPMs in the modulation of host responses to various infectious diseases, and hence can be ventured as a new therapeutic opportunity for treating infectious inflammatory diseases, and to curtail the usage of antibiotic therapy, with prime focus to overcome antimicrobial resistance (Zhao et al., 2021; ; ).
SPMs in bacterial infection
Studies conducted on bacterial infection models revealed varied levels of SPMs. A non-human primate model of pulmonary infection showed notable decrease in levels of RvE1 in blood, when the infection was induced by Streptococcal pneumonia (). Similarly, lowered RvD1 levels were present in a rodent model of Pseudomonas aeruginosa induced pneumonia (). These incidences seem to suggest that a drop in the formation of SPMs is involved in pathogenicity of pneumonia. A compilation of results from several studies imply that increased production of SPMs is important in host defense for bacterial clearance and infection resolution (; ; Thornton and Yin, 2021). Conversely, inability to survive infections could be attributed to a failure to resolve the inflammatory response, owing to the decrease in SPM levels (). Though dietary precursors of SPMs are capable of raising their levels, use of pure SPMs may be required in cases of acute bacterial infections (Thornton and Yin, 2021). RvD2 and LxA4 are prime candidates for this purpose, as their effectiveness has been established in preclinical rodent models, and they have no correlation with sepsis non-survivors (Walker et al., 2011; ; ). Other studies have suggested the role of endogenously formed SPMs in the pathophysiology of bacterial infection. They also point to specific SPMs as biomarkers to assess disease severity (). The majority of research into the utility of SPMs as therapeutic compounds have focused on their antibiotic mechanisms, optimal dose and timing of administration in order to maximize their effectiveness (Thornton and Yin, 2021). Using these compounds to combat bacterial infection might reduce the world’s dependence on antibiotics, and potentially alleviate the evolving global crisis of antimicrobial resistance (; Thornton and Yin, 2021), as discussed in Table 1.
TABLE 1
| SPM | Role | Mediators | Receptors | Examples of infection |
|---|---|---|---|---|
| Bacterial infections | Reducing neutrophils migration and declining pro-inflammatory T cell activity (Thornton and Yin, 2021) | Lipoxins | RvE1 | Mycobacterium Tuberculosis, Salmonella spp., Sepsis, Escherichia coli, Staphylococcus aureus and Streptococcal pneumonia |
| Resolvins | RvD1 | |||
| RvD2 | ||||
| LxA4 | ||||
| Virus infections | Inhibits viral RNA nuclear export, rise antibody production by augmenting B-cell differentiation to an antibody secreting B-cell (; ; ; ; ; ) | Lipoxins | LxA4 | Influenza A, RSV, HIV, HSV |
| Resolvins | D1 | |||
| Protectins | D2 | |||
| Parasitic infections | Decrease of recruitment of neutrophils, lymphocytes and eosinophils () | Lipoxins | IL12 | Toxoplasma gondii, Angiostrongylus costaricensis, Plasmodium spp. and Trypanosoma cruzi |
| LxA4 | ||||
| IFNγ |
SPMs influence host defense and infectious inflammation.
SPMs in viral infections
Viruses, being obligate parasites, must infect target cells and highjack their cellular machinery to replicate. The stages involved in this process constitute the viral life cycle. These are: entry, genome replication, and exit (Ryu, 2017; ). The first of these stages can be subdivided into attachment, penetration and uncoating, while the last one includes virion assembly and release. SPMs are known to affect the inflammatory response generated in response to a viral infection and their basic roles, mediators and receptors are depicted in Table 1. However, studies that examine the direct effect of these molecules on viral life cycle are very few. There has been a recent report of LXA4 being able to influence the life cycle of Kaposi’s Sarcoma-Associated Herpesvirus (KSHV). This is achieved through chromatin modulation and hedgehog signaling, and the net result is that the dormancy of the virus is destabilized and the expression of programmed death-ligand 1 (PD-L1) is reduced in Kaposi’s sarcoma. As a result of these effects immune evasion is reduced (). On the other hand, there are more than a few reports of SPM receptors acting as receptors for viruses as well. This intersection of host immune system with points in viral infection pathway presents new opportunities for utilizing SPMs. Provided that the duration of necessary immune response and the point at which the response must be suppressed can be determined, SPMs can be used to prevent damage to the host. More research is needed to determine these parameters and to employ these mediators in case of viral infection ().
SPMs in parasitic infections
SPMs do play a part in the immune response elicited by parasitic infections. An intense response involving dendritic cells (DCs) and production of IL-12 takes place during infection by Toxoplasma gondii (Reis e Sousa et al., 1997). Lipoxins produced during toxoplasmosis employ an autocoid mechanism on DCs via ALX, through which expression of CCR5 and IL-12 production are attenuated () as depicted in Table 1. Also, lowered levels of 5-LOX in animal models can result in higher amounts of IL-2 and IFNγ relative to those of wild-type animals, severe encephalitis and increased risk of death, which can all be relieved through the introduction of LXA4 analogues (). Administration of lipoxins is also reported to aid host defense in case of both intracellular and extracellular parasitic infection, including Angiostrongylus costaricensis (), Plasmodium spp. (Shryock et al., 2013) and Trypanosoma cruzi ().
SPMs in regulation of inflammatory macrophages in COVID-19
Macrophages in COVID-19
Macrophages (MΦ) are heterogenous family of innate immune cells (). MΦs are tissue-resident or infiltrated/inflammatory hemopoietic cells of myeloid origin, known to exist in every tissue of the body, and exhibit organ specific functions (). Macrophages are phagocytic in nature, perform a diverse array of functions by integrating the cues from various cellular signals that arise in response to varied stimuli (injury/pathogen) (). Macrophages are essential for innate immunity, to maintain tissue integrity and homeostasis, in the development of normal tissue, and are also critical in resolution of inflammation (). They phagocytose apoptotic neutrophils by efferocytosis, help in repair of tissue following injury. They are also mediators in fibrosis, tumor growth and immunosuppression (). MΦs exhibit their functions by promoting release of proinflammatory mediators, presenting antigens to naive T lymphocytes thereby stimulating adaptive immune response in the tissue (). Macrophages are named based on their tissue precise location, such as Kupffer cells (liver), microglial cells (brain), Hofbauer cells (placenta), osteoclasts (bone), alveolar macrophages, pneumocytes type II (lung), Serous macrophages (serous cavities), histiocytes (connective tissue), Langerhans cells (LC) (skin), Synovial cells (type A) (Joints/cartilage) etc (). Additionally, macrophages can be classified into two varied phenotypes based on their functional heterogeneity as: classically stimulated pro-inflammatory macrophages (M1) and alternatively stimulated anti-inflammatory macrophages (M2) (). These phenotypic variants differ in their cytokine production, expression of receptors on their surface. Macrophages can be categorized or polarized to M1 pro-inflammatory phenotype by IFN-γ, tumor necrosis factor alpha (TNFα) and lipopolysaccharide (LPS) (). Activated M1 macrophages stimulate production and release of TNFα, L-6, IL-12, IL-1β and IL-23, along with monocyte chemotactic protein 1 (MCP-1), chemokine CCL8, macrophage inflammatory protein 2 (MIP-2), ROS, nitric oxide (NO), CD16, and CD32 () as depicted in Figure 1. M1 polarization of macrophages is essential for viral clearance, enhance antiviral immunity due to release of cytokines and infiltration of polymorphonuclear leukocytes (PMN) and dendritic cells, have robust antimicrobial, antitumor activities, and mediate TH1 response. The polarization of M2 macrophages, occurs in response to transforming growth factor beta (TGF-β) and TH2 cytokines (IL-4, IL-13) and anti-inflammatory cytokines IL-10. M2 macrophages perform immune regulation, anti-inflammation, wound healing and tissue repair (). M2 macrophages exhibit enhanced levels of IL-1 receptor antagonist (IL-1RA), arginase 1 (Arg-1), IL-10, TGF-β, Chitinase-3-Like Protein 3 or Ym1,CCL18, and low production of IL-12 phenomenon. M2 macrophages also express CD206 (C-Type Mannose Receptor 1) and CD163 (Hemoglobin-Haptoglobin Scavenger Receptor) (Rőszer, 2015). The polarization to pro-inflammatory and antimicrobial M1 macrophages must be inhibited to prevent further collateral host tissue damage.
FIGURE 1
SARS-COV2 caused disastrous COVID-19 pandemic that claimed several millions of lives. The overwhelmed death rate associated with COVID-19 was mainly attributed to acute respiratory distress syndrome (ARDS), cytokine storm and fatal multi-organ failure. Other pathological events observed in COVID-19 cases are disseminated intravascular coagulation (DIC) syndrome, edema, and pneumonia, which are prime consequences of macrophage activation syndrome (MAS) (). Angiotensin-converting enzyme 2 (ACE2) receptors are essential for entry of SARS-COV2, and are found to be prominently expressed on the surface of alveolar macrophages (AMs), suggesting that lungs are the prime direct target of SARS-CoV-2 mediated pathogenesis (). Lung macrophages include two subtypes: alveolar macrophages which lie in close vicinity to type I and type II epithelial alveolar cells, and interstitial macrophages (IMs), which are located between alveolar epithelial zone and capillary bed (Shirey et al., 2014; ). Ontogeny of both subtypes varies, IMs are derived from adult hematopoiesis and replenished from blood Ly6Chi (lymphocyte antigen 6c) monocytes. Moreover, a large proportion of AMs are derived from fetal liver monocytes, with smaller proportions from yolk sac–derived progenitors and bone marrow-derived monocytes (). Nevertheless, in presence of an inflammatory stimuli AMs can be repopulated from circulating blood Ly6Chimonocytes. Additionally both IMs and AMs can be categorized in to two phenotypes (M1 and M2), therefore, M1 AMs, M2 AMs and M1 IMs and M2 IMs are different subtypes known to exist (Tamoutounour et al., 2013).
AMs are located in pulmonary airspaces, constitute nearly ∼95% of the alveolar immune cells. AMs are crucially required to maintain lung homeostasis via clearing pulmonary surfactant and cellular debris, essential for tissue repair and resolution of inflammation (). They phagocytose inhaled irritants and are the first cells to respond to pathogens, hence are known as alveolar guardians/scavengers. CD68 (“scavenger receptor”) was highly expressed in AMs. AMs phagocytose invading pathogen, entering lungs in lesser proportion, by crawling via pores of Kohn under influence of chemotaxis (). In physiological state, AMs exist in M2 phenotype articulating the cell-surface protein mannose receptor C type 1 (MRC1, CD206). Moreover, in pathogenic conditions i.e. in response to varied stimuli (injury/pathogen), AMs rapidly shift from M2 phenotype to M1 phenotype owing to their highly plastic nature. In SARS-COV2 viral RNA or DNA components act as pathogen connected molecular-patterns—(PAMPs), which activate AMs toward the M1 phenotype of macrophages readily (Wang et al., 2022). M1 AMs enable the SARS-CoV-2 to smoothly enter, and replicate in the lungs. This might be due to low endosomal pH and enhanced cellular softness. NP a structural protein of SARS-CoV-2 is essential for the assembly of the nucleocapsid and the release of virions, which is highly expressed in M1AMs (). CD206 is a typical M2 marker limiting viral spread. Intriguingly, M2 AMs exist in lower lysosomal pH, mobilize more acidic lysosomes for viral degradation, thereby limit SARS –COV2 spread i.e.M2 AMs exhibit antiviral/anti-inflammatory effects (; Zhang et al., 2021).
SPMs in COVID-19
Infection with SARS-CoV2 is attributed with increase in chemical mediators such as IL-6, C-reactive protein, D-Dimers, fibrinogen and erythrocyte sedimentation rate (). In COVID-19 infections, there is exaggerated production of proinflammatory lipid mediators like cytokines, chemokines and leukotrienes (LTB4) (; ), also it is prominently observed that endogenous SPM production is dysregulated in vivo (). It is reported that SARS-CoV-2 infected patients are at an increased risk due to thrombotic events. Hence management of COVID-19 patients with prophylactic anticoagulant or thrombolytic agents is crucial. It was reported that administration of resolvin D4 (RvD4), an SPM, stimulated thrombus resolution by decreasing neutrophil infiltration, and upregulating apoptosis of PMN, promoting further synthesis of D-series resolvins involved in inflammation resolution (). Resolvin D1 and Resolvin D2 are known to reduce viral spike protein induced production of pro-inflammatory cytokines and chemokines (Recchiuti et al., 2021). Lipoxin (LXA4), methyl ester-benzo-lipoxin A4 (BLXA4), resolvin (RvE1) may be used to treat gingival inflammation (). In COVID-19 patients with cardiovascular complications, the omega-3 essential fatty acids can be used as an adjuvant therapy (). Interestingly in a randomized clinical trial using high-dose n-3 PUFA supplementation (1.5 g/day EPA and 1.0 g/day DHA), it was reported that, n-3 PUFAs might exert direct modulatory effects on the chemical mediators responsible to cause the cytokine storm such as IL-6, IL-1β and TNF-α (Tan et al., 2018). Resolvins inhibit neutrophil infiltration by decreasing expression of surface adhesion receptors such as CD11b, CD18 on PMN, also capable of decreasing the release of IL-8chemokine.Resolvin E1 inhibits mitogen -activated protein kinase (MAPK)and NF-κB pathways, reduce PMN infiltration and cytokine release and can be used for treatment of sepsis induced cardiomyopathy (Zhang et al., 2020). Maresin1 and its epoxide intermediate 13S, 14S-epoxi-DHA, enhance the macrophage conversion from M1 to M2 phenotype, it is well known that M2 are pro-resolving in nature, enhance macrophage phagocytosis and efferocytosis (). Lipoxins (LXs) might reduce the inflammatory changes that occur due to activation of MAPK, mTOR, and NLPR3 inflammasome in COVID-19, reduce tumor necrosis factor-alpha and interferon-gamma secretion, block T cell migration and promote T cell apoptosis (). Neuroprotectin D1/Protectin reduce PMN infiltration through endothelial cells and stimulate the removal of apoptotic cells by MΦ t have crucial hereby play a crucial role in managing diseases such as Alzheimer’s disease (; ). It was reported that SPMs could enhance antiviral B lymphocytic activity during viral infections like influenza. Additionally, SPM precursors such as 17-hydroxy docosahexaenoic acid (17-HDHA) enhance immune responses against influenza infections hence could be used as vaccine adjuvants ().
These findings using several invivo and invitro models highlight the therapeutic potential of SPMs. They can be used as adjuvants to anti-inflammatory agents, or can act as agonists and enhance the pro-resolving actions of endogenous mediators. Hence can be best used as novel therapeutic molecules to combat infection as in the case of COVID-19.
SPMs in macrophage regulation
Macrophages are the crucial players of the inflammatory milieu that arise due to COVID-19. They are regarded as the first line of immune defense, as they mediate between innate immunity and adaptive immunity responses. Moreno-Eutimio et al., demonstrated that host toll-like receptors (TLRs) specifically TLR7/8 is an invader sensing receptor able to recognize ssRNA sequences of SARS –COV2, this recognition could stimulate M1 pro-inflammatory macrophages which may trigger a rapid type I IFNs(interferon) response, consequently causing innate immune hyperactivation, aberrant cytokine production and ultimately lead to acute lung injury (ALI), ARDS, multi-organ fibrosis and dysfunction (). Elevated levels of infiltrated macrophages with subsequent overproduction of pro-inflammatory cytokines are correlated with clinical manifestations of COVID-19.
Lipoxins (LXs), can inhibition of viral entry and its replication, downregulate ACE2 receptors, inhibit release of the pro-inflammatory cytokines. Moreover, LXs can augment the polarization of macrophages from (M1) to (M2) phenotype, causing a shift from pro-inflammatory to anti-inflammatory environment, thereby enhancing the inflammation resolving actions of macrophages in SARS-CoV-2 infection (; ). RvE1and RvE4 enhances macrophage phagocytosis and efferocytosis of senescent erythrocytes that characterize COVID-19 (). RvE3 decreases allergic airway inflammation via the IL-23/IL-17A pathway (Sato et al., 2019).
During acute inflammation, biosynthesis of SPMs, specifically resolvin D1 [RvD1] and RvD5) was enhanced due to overexpression of miR-466l in macrophages, which ultimately enhanced resolution of inflammation, efficiently demonstrated in mice models by Li et al. (). RvD1 and RvD2 subside MΦ-driven inflammation via potentiating MΦ phagocytosis, decreasing release of pro-inflammatory cytokines and chemokines from MΦ, in response to the viral spike protein (Recchiuti et al., 2021). Maresins (MaRs) can resolve inflammation by stimulating macrophage phagocytosis of neutrophils (Weill et al., 2020). Maresins 13S, 14S-epoxy-maresin intermediate generated during synthesis of Maresin (MaR1) is bioactive and stimulates the phenotype transition from M1 to M2 macrophages (Serhan et al., 2022). RvD6 isomer and Elovanoid-N32 reduced expression of the ACE2 receptors and blocked the receptor binding domain of the virus spike protein thereby preventing receptor-virus interactions, reducing pro-inflammatory cytokine release (). The protectin (PD) family of mediators regulate viral propagation by inhibiting intracellular viral RNA transport mechanisms. Neuroprotectin D1/Protectin D1 exerts anti-inflammatory/pro-resolving effects by suppressing oxidative stress, Aβ42 production as observed in pathologies like retinal degenerations, stroke, and Alzheimer’s disease ().
SPMs in cytokine regulation
SARS-CoV-2 triggers cytokine production in overabundance, resulting in exaggerated inflammatory response and an avalanche of cytokines, dubbed “cytokine storm” (CS) or “quasi cytokine storm” in patients with COVID-19 (). CS can lead to persistent fever, muscle pain, hypotension, endothelial dysfunction, thromboembolic events, hypercoagulation, and cardiovascular complications, and in even more severe cases, to ALI/ARDS, hemophagocytic lymphohistiocytosis (HLH), multiple organ dysfunction and eventually death (Yang, L et al., 2021; Yang et al., 2020). CS can, therefore, serve as a measure of disease progression and severity (Tang Y et al., 2020). SARS-CoV-2 infection was found to result in elevated levels of pro inflammatory mediators such as interleukins (IL) (a pro-inflammatory cytokine mediator), tumour necrosis factor-α (TNF-α), CCL5, CXCL9, CXCL10, and CXCL11. Among IL, increase in levels were specifically found among IL-1β, IL-6, IL-7, IL-8, IL-9, IL-10, IL-13, IL-15, IL-17, IL-18, IL-29, IL-1ra, IL-2, IL-2Rα (Figure 1) (; ). Severe cases of the disease resulted in increased levels of CCL7, CCL3, and CXCL9, while quantities of CXCL10, CCL2, and CCl3 were higher in patients admitted to the ICU. Compared to this, moderate cases showed elevated levels of IL-18, IP-10, and M-CSF. IL-6, IL-7, IL-10, G-CSF, IP-10, MCP-1, MIP-1α, IL-18, MCP-3, M-CSF, and MIG. Other than these, CXCL12, CXCL1, CCL11, and the chemokine CCL27 were also elevated in COVID-19 patients (). Another study reported higher serum levels of IL-6, IL-7, IL-10, granulocyte colony-stimulating factor (G-CSF), M-CSF, IP-10, monocyte chemoattractant protein-1 (MCP-1), MCP-3, MIG, and macrophage inflammatory protein 1α (MIP1α) is severe COVID-19 patients. All of these cytokines might be useful in predicting the severity of the disease (). Initial studies on COVID-19 patients showed that cytokine levels were enhanced in ICU patients as compared to non-ICU patients (). In another study it was reported that sharply elevated IL-6 cytokine levels were observed in critically ill patients (; ).
Pro-resolving mediators such as SPMs can be used to counter CS in cases of severe COVID-19 (). Resolvin D1 and Resolvin D2 are especially useful in this regard due to their ability to reduce the levels of TNF-α, IL-8 and MIP-1, and attenuate the effects of CS (Recchiuti et al., 2021). Other SPMs that can reduce cytokine production include: RvD1, which achieves this result by downregulation of the NF-κB pathway (); RvE1, which reduces the levels of IL-8 and TNFα production; and LXs, which might inhibit the TLR-4/MyD88 axis activated during COVID-19 and reduce hyperinflammation and CS-induced effects (Tang Y et al., 2020). LXs in particular are also known to inhibit IL-6 and TNF-α production, while LXA4 inhibits iNOS, NF-kB, MAPK and COX-2 and enhance NRF2 genes expression (Zhang et al., 2022). All these SPMs could be of therapeutic application during SARS-COV-2 infection. Other SPMs with similar benefits include Resolvin E1 and LXA4 (capable of suppressing IL-23 and IL-17, IL-6 and TNF-α); PDX and NPD1 (decreases secretion of TNF-α, IL-6, IL-1β, CXCL-1, CXCL-2 and NOS-2) (). Finally, there are RvD2 and Mar1, called block inflammasome components, and can cause notable reduction in potent pro-inflammatory cytokine IL-1β ().
Conclusion and future prospective
The major reason for severity of COVID-19 infection is attributed to the acute uncontrolled inflammatory response in the lungs known as cytokine storm. The macrophages play important role in regulating COVID-19 inflammation by switching between two forms: pro-inflammatory macrophages (M1) and anti-inflammatory macrophages (M2) forms. Since the lungs are preferred target of most respiratory viruses including COVID-19 so the involvement of lung alveolar macrophages in progression of severe SARS-COV 2 is eminent. ACE2 receptors are essential for entry of SARS-COV2, and are found to be expressed on alveolar macrophages (AMs). The shifting of alveolar macrophages from M2 to M1 form triggers the SARS-COV 2 virus to smoothly infect the lungs, replicate and consequently induce cytokine storm. This causes build-up of oedema i.e. accumulation of inflammatory fluids in lungs that averts oxygen transfer from lungs towards blood capillaries inducing hypoxia and if untreated then associated multiple organ failure. The specialized pro-resolving lipid mediators are found to be highly effective in inhibiting inflammatory responses during infection. They are produced by innate immune cells from essential long chain fatty acids and are found to improve the concentration of anti-inflammatory lipid mediators. The specialized pro resolving lipid mediators such as protectins, lipoxins and resolvins have been strongly associated with inhibition of cytokine avalanche or cytokine storm which is a well-known reason behind COVID-19 deaths. The viral diseases have been always difficult to treat due to numerous factors such as limited anti-viral pharmaceutical agents, frequent re-infections, frequent mutations in RNA viruses and restructuring of genome etc. but SPM’s offers a different approach of treatment wherein we can control severity of infection by controlling inflammation. This is well justified by the fact that most viral infections subside on their own after completion of their cycles in host. Infact the majority of Covid patients developed mild symptoms possibly due to absence of inflammatory responses as cytokine storm. So in near future regulating the respiratory inflammation shall be the goal in order to avoid progression to severe respiratory distress. Thus there is great scope of using SPM’s against COVID-19 variants and also other viral infections in near future particularly RNA viruses which evades novel pharmaceutical agents due to their mutagenic capabilities.
Statements
Author contributions
VK and NY conceptualized the idea of this review and responsible for the entire manuscript in its final form. AAC, ASA, MA-Z, NSB, SH, MDG, AP, SSL, and PKS checked the complete manuscript in term of technical and scientific integrity. All authors contributed to manuscript writing, revision, read, and approved the submitted version.
Funding
The funding was provided by the Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University (IMSIU) for supporting this work through Research Group No. RG-21-09-90.
Acknowledgments
Authors would like to thank Director (Prof. Vinay Sharma) and Deputy Director (Prof. Ajay Jain), Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur providing the needful facilities and guidelines to write this important manuscript. The authors also extend their appreciation to the Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University (IMSIU) for funding and supporting this work through Research Group No. RG-21-09-90.
Conflict of interest
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.
Publisher’s note
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.
References
1
AbassiZ.KnaneyY.KarramT.HeymanS. N. (2020). The lung macrophage in SARS-CoV-2 infection: A friend or a foe?Front. Immunol.11, 1312. 10.3389/fimmu.2020.01312
2
AbbasiS.PendergrassL. B.LeggiadroR. J. (1994). Influenza complicated by Moraxella catarrhalis bacteremia. Pediatr. Infect. Dis. J.13 (10), 937–938. 10.1097/00006454-199410000-00022
3
AdebisiY. A.AlaranA. J.OkerekeM.OkeG. I.AmosO. A.OlaoyeO. C.et al (2021). COVID-19 and antimicrobial resistance: A review. Infect. Dis.14, 11786337211033870. 10.1177/11786337211033870
4
AfshinnekooE.BhattacharyaC.Burguete-GarcíaA.Castro-NallarE.DengY.DesnuesC.et al (2021). COVID-19 drug practices risk antimicrobial resistance evolution. Microbe2 (4), e135–e136. 10.1016/S2666-5247(21)00039-2
5
AkagiD.ChenM.ToyR.ChatterjeeA.ConteM. S. (2015). Systemic delivery of proresolving lipid mediators resolvin D2 and maresin 1 attenuates intimal hyperplasia in mice. FASEB J.29 (6), 2504–2513. 10.1096/fj.14-265363
6
AlibertiJ.SerhanC.SherA. (2002). Parasite-induced lipoxin A4 is an endogenous regulator of IL-12 production and immunopathology in Toxoplasma gondii infection. J. Exp. Med.196 (9), 1253–1262. 10.1084/jem.20021183
7
AlibertiJ.HienyS.Reis e SousaC.SerhanC. N.SherA. (2002). Lipoxin-mediated inhibition of IL-12 production by DCs: A mechanism for regulation of microbial immunity. Nat. Immunol.3 (1), 76–82. 10.1038/ni745
8
AllenB. L.Montague-CardosoK.SimeoliR.ColasR. A.OggeroS.VilarB.et al (2020). Imbalance of proresolving lipid mediators in persistent allodynia dissociated from signs of clinical arthritis. Pain161 (9), 2155–2166. 10.1097/j.pain.0000000000001908
9
AngrimanF.FerreyroB. L.BurryL.FanE.FergusonN. D.HusainS.et al (2021). Interleukin-6 receptor blockade in patients with COVID-19: Placing clinical trials into context. Respir. Med.9 (6), 655–664. 10.1016/S2213-2600(21)00139-9
10
AshaK.BalfeN.Sharma-WaliaN. (2020). Concurrent control of the kaposi's sarcoma-associated Herpesvirus life cycle through chromatin modulation and host hedgehog signaling: A new prospect for the therapeutic potential of lipoxin A4. J. virology94 (9), 021777–e2219. 10.1128/JVI.02177-19
11
AtriC.GuerfaliF. Z.LaouiniD. (2018). Role of human macrophage polarization in inflammation during infectious diseases. Int. J. Mol. Sci.19 (6), 1801. 10.3390/ijms19061801
12
BaltaM. G.PapathanasiouE.ChristopoulosP. F. (2021). Specialized pro-resolving mediators as potential regulators of inflammatory macrophage responses in COVID-19. Front. Immunol.12, 632238. 10.3389/fimmu.2021.632238
13
Bandeira-MeloC.SerraM. F.DiazB. L.CordeiroR. S.SilvaP. M.LenziH. L.et al (2000). Cyclooxygenase-2-derived prostaglandin E2 and lipoxin A4 accelerate resolution of allergic edema in Angiostrongylus costaricensis-infected rats: Relationship with concurrent eosinophilia. J. Immunol.164 (2), 1029–1036. 10.4049/jimmunol.164.2.1029
14
BasilM. C.LevyB. D. (2016). Specialized pro-resolving mediators: Endogenous regulators of infection and inflammation. Nat. Rev. Immunol.16 (1), 51–67. 10.1038/nri.2015.4
15
BatihaG. E.Al-GareebA. I.ElekhnawyE.Al-KuraishyH. M. (2022). Potential role of lipoxin in the management of COVID-19: A narrative review. Inflammopharmacology30, 1993–2001. 10.1007/s10787-022-01070-3
16
BazanN. G. (2009). Neuroprotectin D1-mediated anti-inflammatory and survival signaling in stroke, retinal degenerations, and Alzheimer's disease. J. lipid Res.50, S400–S405. 10.1194/jlr.R800068-JLR200
17
BissonnetteE. Y.Lauzon-JosetJ. F.DebleyJ. S.ZieglerS. F. (2020). Cross-talk between alveolar macrophages and lung epithelial cells is essential to maintain lung homeostasis. Front. Immunol.11, 583042. 10.3389/fimmu.2020.583042
18
BoerlinP.Reid-SmithR. J. (2008). Antimicrobial resistance: Its emergence and transmission. Animal health Res. Rev.9 (2), 115–126. 10.1017/S146625230800159X
19
BosvielR.Joumard-CubizollesL.Chinetti-GbaguidiG.BayleD.CopinC.HennuyerN.et al (2017). DHA-derived oxylipins, neuroprostanes and protectins, differentially and dose-dependently modulate the inflammatory response in human macrophages: Putative mechanisms through PPAR activation. Free Radic. Biol. Med.103, 146–154. 10.1016/j.freeradbiomed.2016.12.018
20
CatanzaroM.FagianiF.RacchiM.CorsiniE.GovoniS.LanniC. (2020). Immune response in COVID-19: Addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2. Signal Transduct. Target. Ther.5 (1), 84. 10.1038/s41392-020-0191-1
21
CDC (2022). COVID-19: U.S. Impact on antimicrobial resistance, special report 2022. Atlanta, GA: U.S. Department of Health and Human Services.
22
ChedidM.WakedR.HaddadE.ChetataN.SalibaG.ChoucairJ. (2021). Antibiotics in treatment of COVID-19 complications: A review of frequency, indications, and efficacy. J. Infect. public health14 (5), 570–576. 10.1016/j.jiph.2021.02.001
23
ChenN.ZhouM.DongX.QuJ.GongF.HanY.et al (2020). Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, China: A descriptive study. Lancet (London, Engl.395 (10223), 507–513. 10.1016/S0140-6736(20)30211-7
24
ChenX.ZhaoB.QuY.ChenY.XiongJ.FengY.et al (2020). Detectable serum severe acute respiratory syndrome coronavirus 2 viral load (RNAemia) is closely correlated with drastically elevated interleukin 6 level in critically ill patients with coronavirus disease 2019. Clin. Infect. Dis.71 (8), 1937–1942. 10.1093/cid/ciaa449
25
CherpokovaD.JouveneC. C.LibrerosS.DeRooE. P.ChuL.de la RosaX.et al (2019). Resolvin D4 attenuates the severity of pathological thrombosis in mice. Blood134 (17), 1458–1468. 10.1182/blood.2018886317
26
ChiY.GeY.WuB.ZhangW.WuT.WenT.et al (2020). Serum cytokine and chemokine profile in relation to the severity of coronavirus disease 2019 in China. J. Infect. Dis.222 (5), 746–754. 10.1093/infdis/jiaa363
27
ChiangN.de la RosaX.LibrerosS.SerhanC. N. (2017). Novel resolvin D2 receptor Axis in infectious inflammation. J. Immunol.198 (2), 842–851. 10.4049/jimmunol.1601650
28
ChiangN.LibrerosS.NorrisP. C.de la RosaX.SerhanC. N. (2019). Maresin 1 activates LGR6 receptor promoting phagocyte immunoresolvent functions. J. Clin. investigation129 (12), 5294–5311. 10.1172/JCI129448
29
ChristakiE.MarcouM.TofaridesA. (2020). Antimicrobial resistance in bacteria: Mechanisms, evolution, and persistence. J. Mol. Evol.88 (1), 26–40. 10.1007/s00239-019-09914-3
30
CillonizC.Pantin-JackwoodM. J.NiC.GoodmanA. G.PengX.ProllS. C.et al (2010). Lethal dissemination of H5N1 influenza virus is associated with dysregulation of inflammation and lipoxin signaling in a mouse model of infection. J. virology84 (15), 7613–7624. 10.1128/JVI.00553-10
31
CodagnoneM.CianciE.LamolinaraA.MariV. C.NespoliA.IsopiE.et al (2018). Resolvin D1 enhances the resolution of lung inflammation caused by long-term Pseudomonas aeruginosa infection. Mucosal Immunol.11 (1), 35–49. 10.1038/mi.2017.36
32
DalliJ.ChiangN.SerhanC. N. (2015b). Elucidation of novel 13-series resolvins that increase with atorvastatin and clear infections. Nat. Med.21 (9), 1071–1075. 10.1038/nm.3911
33
DalliJ.ColasR. A.QuintanaC.Barragan-BradfordD.HurwitzS.LevyB. D.et al (2017). Human sepsis eicosanoid and proresolving lipid mediator temporal profiles: Correlations with survival and clinical outcomes. Crit. care Med.45 (1), 58–68. 10.1097/CCM.0000000000002014
34
DalliJ.KraftB. D.ColasR. A.ShinoharaM.FredenburghL. E.HessD. R.et al (2015a). The regulation of proresolving lipid mediator profiles in baboon pneumonia by inhaled carbon monoxide. Am. J. Respir. Cell Mol. Biol.53 (3), 314–325. 10.1165/rcmb.2014-0299OC
35
DarweshA. M.BassiouniW.SosnowskiD. K.SeubertJ. M. (2021). Can N-3 polyunsaturated fatty acids be considered a potential adjuvant therapy for COVID-19-associated cardiovascular complications?Pharmacol. Ther.219, 107703. 10.1016/j.pharmthera.2020.107703
36
DasU. N. (2021). Bioactive lipids in COVID-19-further evidence. Archives Med. Res.52 (1), 107–120. 10.1016/j.arcmed.2020.09.006
37
de la RosaX.NorrisP. C.ChiangN.RodriguezA. R.SpurB. W.SerhanC. N. (2018). Identification and complete stereochemical assignments of the new resolvin conjugates in tissue regeneration in human tissues that stimulate proresolving phagocyte functions and tissue regeneration. Am. J. pathology188 (4), 950–966. 10.1016/j.ajpath.2018.01.004
38
Di BenedettoP.RuscittiP.VadaszZ.ToubiE.GiacomelliR. (2019). Macrophages with regulatory functions, a possible new therapeutic perspective in autoimmune diseases. Autoimmun. Rev.18 (10), 102369. 10.1016/j.autrev.2019.102369
39
DockrellD. H.RussellC. D.McHughB.FraserR. (2022). Does autonomous macrophage-driven inflammation promote alveolar damage in COVID-19?Eur. Respir. J.60, 2201521. 10.1183/13993003.01521-2022
40
DoolittleW. F. (1998). You are what you eat: A gene transfer ratchet could account for bacterial genes in eukaryotic nuclear genomes. Trends Genet. TIG14 (8), 307–311. 10.1016/s0168-9525(98)01494-2
41
EgyirB.Obeng-NkrumahN.KyeiG. B. (2020). COVID-19 pandemic and antimicrobial resistance: Another call to strengthen laboratory diagnostic capacity in Africa. Afr. J. laboratory Med.9 (1), 1302. 10.4102/ajlm.v9i1.1302
42
FreedmanC.TranA.TourdotB. E.KalyanaramanC.PerryS.HolinstatM.et al (2020). Biosynthesis of the maresin intermediate, 13S,14S-Epoxy-DHA, by human 15-lipoxygenase and 12-lipoxygenase and its regulation through negative allosteric modulators. Biochemistry59 (19), 1832–1844. 10.1021/acs.biochem.0c00233
43
GalloC. G.FiorinoS.PosabellaG.AntonacciD.TropeanoA.PausiniE.et al (2022). The function of specialized pro-resolving endogenous lipid mediators, vitamins, and other micronutrients in the control of the inflammatory processes: Possible role in patients with SARS-CoV-2 related infection. Prostagl. other lipid Mediat.159, 106619. 10.1016/j.prostaglandins.2022.106619
44
GeY.HuangM.YaoY. M. (2022). Efferocytosis and its role in inflammatory disorders. Front. Cell Dev. Biol.10, 839248. 10.3389/fcell.2022.839248
45
GenisP.JettM.BerntonE. W.BoyleT.GelbardH. A.DzenkoK.et al (1992). Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions: Implications for the neuropathogenesis of HIV disease. J. Exp. Med.176 (6), 1703–1718. 10.1084/jem.176.6.1703
46
GuilliamsM.SvedbergF. R. (2021). Does tissue imprinting restrict macrophage plasticity?Nat. Immunol.22 (2), 118–127. 10.1038/s41590-020-00849-2
47
HanH.MaQ.LiC.LiuR.ZhaoL.WangW.et al (2020). Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg. microbes Infect.9 (1), 1123–1130. 10.1080/22221751.2020.1770129
48
HasturkH.SchulteF.MartinsM.SherzaiH.FlorosC.CuginiM.et al (2021). Safety and preliminary efficacy of a novel host-modulatory therapy for reducing gingival inflammation. Front. Immunol.12, 704163. 10.3389/fimmu.2021.704163
49
HoffmannM.Kleine-WeberH.SchroederS.KrügerN.HerrlerT.ErichsenS.et al (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell181 (2), 271–280. 10.1016/j.cell.2020.02.052
50
HojyoS.UchidaM.TanakaK.HasebeR.TanakaY.MurakamiM.et al (2020). How COVID-19 induces cytokine storm with high mortality. Inflamm. Regen.40, 37. 10.1186/s41232-020-00146-3
51
HuangC.WangY.LiX.RenL.ZhaoJ.HuY.et al (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet (London, Engl.395 (10223), 497–506. 10.1016/S0140-6736(20)30183-5
52
HuangI.PranataR.LimM. A.OehadianA.AlisjahbanaB. (2020). C-Reactive protein, procalcitonin, D-dimer, and ferritin in severe coronavirus disease-2019: A meta-analysis. Ther. Adv. Respir. Dis.14, 1753466620937175. 10.1177/1753466620937175
53
ItalianiP.BoraschiD. (2015). New insights into tissue macrophages: From their origin to the development of memory. Immune Netw.15 (4), 167–176. 10.4110/in.2015.15.4.167
54
JacobsJ. H.ViboudC.TchetgenE. T.SchwartzJ.SteinerC.SimonsenL.et al (2014). The association of meningococcal disease with influenza in the United States, 1989-2009. PloS one9 (9), e107486. 10.1371/journal.pone.0107486
55
JafarzadehA.ChauhanP.SahaB.JafarzadehS.NematiM. (2020). Contribution of monocytes and macrophages to the local tissue inflammation and cytokine storm in COVID-19: Lessons from SARS and MERS, and potential therapeutic interventions. Life Sci.257, 118102. 10.1016/j.lfs.2020.118102
56
JiaL.XieJ.ZhaoJ.CaoD.LiangY.HouX.et al (2017). Mechanisms of severe mortality-associated bacterial Co-infections following influenza virus infection. Front. Cell. Infect. Microbiol.7, 338. 10.3389/fcimb.2017.00338
57
KangJ. W.LeeS. M. (2016). Resolvin D1 protects the liver from ischemia/reperfusion injury by enhancing M2 macrophage polarization and efferocytosis. Biochimica Biophysica Acta (BBA)-Molecular Cell Biol. Lipids1861 (9), 1025–1035. 10.1016/j.bbalip.2016.06.002
58
KatsuradaN.SuzukiM.AoshimaM.YaegashiM.IshifujiT.AsohN.et al (2017). The impact of virus infections on pneumonia mortality is complex in adults: A prospective multicentre observational study. BMC Infect. Dis.17 (1), 755. 10.1186/s12879-017-2858-y
59
KnightG. M.GloverR. E.McQuaidC. F.OlaruI. D.GallandatK.LeclercQ. J.et al (2021). Antimicrobial resistance and COVID-19: Intersections and implications. eLife10, e64139. 10.7554/eLife.64139
60
KolliniatiO.IeronymakiE.VergadiE.TsatsanisC. (2022). Metabolic regulation of macrophage activation. J. innate Immun.14 (1), 51–68. 10.1159/000516780
61
KosyrevaA.DzhalilovaD.LokhoninaA.VishnyakovaP.FatkhudinovT. (2021). The role of macrophages in the pathogenesis of SARS-CoV-2-associated acute respiratory distress syndrome. Front. Immunol.12, 682871. 10.3389/fimmu.2021.682871
62
LavinY.MeradM. (2013). Macrophages: Gatekeepers of tissue integrity. Cancer Immunol. Res.1 (4), 201–209. 10.1158/2326-6066.CIR-13-0117
63
LeeC. H. (2021). Role of specialized pro-resolving lipid mediators and their receptors in virus infection: A promising therapeutic strategy for SARS-CoV-2 cytokine storm. Archives pharmacal Res.44 (1), 84–98. 10.1007/s12272-020-01299-y
64
LendeckelU.VenzS.WolkeC. (2022). Macrophages: Shapes and functions. Chemtexts8 (2), 12. 10.1007/s40828-022-00163-4
65
LiY.DalliJ.ChiangN.BaronR. M.QuintanaC.SerhanC. N. (2013). Plasticity of leukocytic exudates in resolving acute inflammation is regulated by MicroRNA and proresolving mediators. Immunity39 (5), 885–898. 10.1016/j.immuni.2013.10.011
66
LibrerosS.ShayA. E.NshimiyimanaR.FichtnerD.MartinM. J.WourmsN.et al (2021). A new E-series resolvin: RvE4 stereochemistry and function in efferocytosis of inflammation-resolution. Front. Immunol.11, 631319. 10.3389/fimmu.2020.631319
67
LobieT. A.RobaA. A.BoothJ. A.KristiansenK. I.AseffaA.SkarstadK.et al (2021). Antimicrobial resistance: A challenge awaiting the post-COVID-19 era. Int. J. Infect. Dis. IJID111, 322–325. 10.1016/j.ijid.2021.09.003
68
LopategiA.Flores-CostaR.RiusB.López-VicarioC.Alcaraz-QuilesJ.TitosE.et al (2019). Frontline Science: Specialized proresolving lipid mediators inhibit the priming and activation of the macrophage NLRP3 inflammasome. J. Leukoc. Biol.105 (1), 25–36. 10.1002/JLB.3HI0517-206RR
69
LvJ.WangZ.QuY.ZhuH.ZhuQ.TongW.et al (2021). Distinct uptake, amplification, and release of SARS-CoV-2 by M1 and M2 alveolar macrophages. Cell Discov.7 (1), 24. 10.1038/s41421-021-00258-1
70
ManoharP.LohB.AthiraS.NachimuthuR.HuaX.WelburnS. C.et al (2020). Secondary bacterial infections during pulmonary viral disease: Phage therapeutics as alternatives to antibiotics?Front. Microbiol.11, 1434. 10.3389/fmicb.2020.01434
71
MehtaP.McAuleyD. F.BrownM.SanchezE.TattersallR. S.MansonJ. J. (2020). COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet (London, Engl.395 (10229), 1033–1034. 10.1016/S0140-6736(20)30628-0
72
MetzgerD. W.SunK. (2013). Immune dysfunction and bacterial coinfections following influenza. J. Immunol.191 (5), 2047–2052. 10.4049/jimmunol.1301152
73
MirandaC.SilvaV.CapitaR.Alonso-CallejaC.IgrejasG.PoetaP. (2020). Implications of antibiotics use during the COVID-19 pandemic: Present and future. J. Antimicrob. Chemother.75 (12), 3413–3416. 10.1093/jac/dkaa350
74
MohammedA.KalleA. M.ReddannaP. (2022). Managing SARS-CoV2 infections through resolution of inflammation by eicosanoids: A review. J. Inflamm. Res.15, 4349–4358. 10.2147/JIR.S355568
75
MolaeiE.MolaeiA.HayesA. W.KarimiG. (2021). Resolvin D1, therapeutic target in acute respiratory distress syndrome. Eur. J. Pharmacol.911, 174527. 10.1016/j.ejphar.2021.174527
76
Molina-BerríosA.Campos-EstradaC.HenriquezN.FaúndezM.TorresG.CastilloC.et al (2013). Protective role of acetylsalicylic acid in experimental trypanosoma cruzi infection: Evidence of a 15-epi-lipoxin A₄-mediated effect. PLoS neglected Trop. Dis.7 (4), e2173. 10.1371/journal.pntd.0002173
77
Moreno-EutimioM. A.López-MacíasC.Pastelin-PalaciosR. (2020). Bioinformatic analysis and identification of single-stranded RNA sequences recognized by TLR7/8 in the SARS-CoV-2, SARS-CoV, and MERS-CoV genomes. Microbes Infect.22 (4-5), 226–229. 10.1016/j.micinf.2020.04.009
78
MoritaM.KubaK.IchikawaA.NakayamaM.KatahiraJ.IwamotoR.et al (2013). The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza. Cell153 (1), 112–125. 10.1016/j.cell.2013.02.027
79
MosserD. M.HamidzadehK.GoncalvesR. (2021). Macrophages and the maintenance of homeostasis. Cell. Mol. Immunol.18 (3), 579–587. 10.1038/s41423-020-00541-3
80
MulcahyM. E.McLoughlinR. M. (2016). Staphylococcus aureus and influenza A virus: Partners in coinfection. mBio7 (6), 020688–e2116. 10.1128/mBio.02068-16
81
MurrayP. J.WynnT. A. (2011). Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol.11 (11), 723–737. 10.1038/nri3073
82
NeupaneA. S.WillsonM.ChojnackiA. K.Vargas E Silva CastanheiraF.MorehouseC.CarestiaA.et al (2020). Patrolling alveolar macrophages conceal bacteria from the immune system to maintain homeostasis. Cell183 (1), 110–125. 10.1016/j.cell.2020.08.020
83
OchiF.TauchiH.JogamotoT.MiuraH.MoritaniT.NagaiK.et al (2018). Sepsis and pleural empyema caused by Streptococcus pyogenes after influenza A virus infection. Case Rep. Pediatr.2018, 4509847. 10.1155/2018/4509847
84
PagetC.TrotteinF. (2019). Mechanisms of bacterial superinfection post-influenza: A role for unconventional T cells. Front. Immunol.10, 336. 10.3389/fimmu.2019.00336
85
PalmasF.ClarkeJ.ColasR. A.GomezE. A.KeoghA.BoylanM.et al (2021). Dysregulated plasma lipid mediator profiles in critically ill COVID-19 patients. PloS one16 (8), e0256226. 10.1371/journal.pone.0256226
86
PhamT. L.HeJ.KakazuA. H.CalandriaJ.DoK. V.NshimiyimanaR.et al (2021). ELV-N32 and RvD6 isomer decrease pro-inflammatory cytokines, senescence programming, ACE2 and SARS-CoV-2-spike protein RBD binding in injured cornea. Sci. Rep.11 (1), 12787. 10.1038/s41598-021-92293-x
87
PidotS. J.GaoW.BuultjensA. H.MonkI. R.GuerillotR.CarterG. P.et al (2018). Increasing tolerance of hospital Enterococcus faecium to handwash alcohols. Sci. Transl. Med.10 (452), eaar6115. 10.1126/scitranslmed.aar6115)
88
QuahJ.JiangB.TanP. C.SiauC.TanT. Y. (2018). Impact of microbial Aetiology on mortality in severe community-acquired pneumonia. BMC Infect. Dis.18 (1), 451. 10.1186/s12879-018-3366-4
89
RajasagiN. K.ReddyP. B.MulikS.GjorstrupP.RouseB. T. (2013). Neuroprotectin D1 reduces the severity of herpes simplex virus-induced corneal immunopathology. Investigative Ophthalmol. Vis. Sci.54 (9), 6269–6279. 10.1167/iovs.13-12152
90
RajasagiN. K.ReddyP. B.SuryawanshiA.MulikS.GjorstrupP.RouseB. T. (2011). Controlling herpes simplex virus-induced ocular inflammatory lesions with the lipid-derived mediator resolvin E1. J. Immunol.186 (3), 1735–1746. 10.4049/jimmunol.1003456
91
RamonS.BakerS. F.SahlerJ. M.KimN.FeldsottE. A.SerhanC. N.et al (2014). The specialized proresolving mediator 17-HDHA enhances the antibody-mediated immune response against influenza virus: A new class of adjuvant?J. Immunol.193 (12), 6031–6040. 10.4049/jimmunol.1302795
92
RastogiM.PandeyN.ShuklaA.SinghS. K. (2020). SARS coronavirus 2: From genome to infectome. Respir. Res.21, 318. 10.1186/s12931-020-01581-z
93
RawsonT. M.MooreL. S. P.ZhuN.RanganathanN.SkolimowskaK.GilchristM.et al (2020). Bacterial and fungal coinfection in individuals with coronavirus: A rapid review to support COVID-19 antimicrobial prescribing. Clin. Infect. Dis.71 (9), 2459–2468. 10.1093/cid/ciaa530
94
RecchiutiA.KrishnamoorthyS.FredmanG.ChiangN.SerhanC. N. (2011). MicroRNAs in resolution of acute inflammation: Identification of novel resolvin D1-miRNA circuits. FASEB J. official Publ. Fed. Am. Soc. Exp. Biol.25 (2), 544–560. 10.1096/fj.10-169599
95
RecchiutiA.PatrunoS.MattoscioD.IsopiE.PomilioA.LamolinaraA.et al (2021). Resolvin D1 and D2 reduce SARS-CoV-2-induced inflammatory responses in cystic fibrosis macrophages. FASEB J. official Publ. Fed. Am. Soc. Exp. Biol.35 (4), e21441. 10.1096/fj.202001952R
96
RegidorP. A.SantosF. G.RizoJ. M.EgeaF. M. (2020). Pro resolving inflammatory effects of the lipid mediators of omega 3 fatty acids and its implication in SARS COVID-19. Med. hypotheses145, 110340. 10.1016/j.mehy.2020.110340
97
Reis e SousaC.HienyS.Scharton-KerstenT.JankovicD.CharestH.GermainR. N.et al (1997). In vivo microbial stimulation induces rapid CD40 ligand-independent production of interleukin 12 by dendritic cells and their redistribution to T cell areas. J. Exp. Med.186 (11), 1819–1829. 10.1084/jem.186.11.1819
98
RőszerT. (2015). Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Mediat. Inflamm.2015, 816460. 10.1155/2015/816460
99
RyuW. S. (2017). Virus life cycle. Mol. Virology Hum. Pathogenic Viruses2017, 31–45. 10.1016/B978-0-12-800838-6.00003-5
100
SatoM.Aoki-SaitoH.FukudaH.IkedaH.KogaY.YatomiM.et al (2019). Resolvin E3 attenuates allergic airway inflammation via the interleukin-23-interleukin-17A pathway. FASEB J. official Publ. Fed. Am. Soc. Exp. Biol.33 (11), 12750–12759. 10.1096/fj.201900283R
101
Schif-ZuckS.GrossN.AssiS.RostokerR.SerhanC. N.ArielA. (2011). Saturated‐efferocytosis generates pro‐resolving CD11blow macrophages: Modulation by resolvins and glucocorticoids. Eur. J. Immunol.41 (2), 366–379. 10.1002/eji.201040801
102
SerhanC. N.DalliJ.KaramnovS.ChoiA.ParkC. K.XuZ. Z.et al (2012). Macrophage proresolving mediator maresin 1 stimulates tissue regeneration and controls pain. FASEB J. official Publ. Fed. Am. Soc. Exp. Biol.26 (4), 1755–1765. 10.1096/fj.11-201442
103
SerhanC. N.LibrerosS.NshimiyimanaR. (2022). E-series resolvin metabolome, biosynthesis and critical role of stereochemistry of specialized pro-resolving mediators (SPMs) in inflammation-resolution: Preparing SPMs for long COVID-19, human clinical trials, and targeted precision nutrition. Seminars Immunol.59, 101597. 10.1016/j.smim.2022.101597
104
SerhanC. N. (2014). Pro-resolving lipid mediators are leads for resolution physiology. Nature510 (7503), 92–101. 10.1038/nature13479
105
ShinM. D.ShuklaS.ChungY. H.BeissV.ChanS. K.Ortega-RiveraO. A.et al (2020). COVID-19 vaccine development and a potential nanomaterial path forward. Nat. Nanotechnol.15 (8), 646–655. 10.1038/s41565-020-0737-y
106
ShireyK. A.LaiW.PletnevaL. M.KarpC. L.DivanovicS.BlancoJ. C.et al (2014). Role of the lipoxygenase pathway in RSV-induced alternatively activated macrophages leading to resolution of lung pathology. Mucosal Immunol.7 (3), 549–557. 10.1038/mi.2013.71
107
ShryockN.McBerryC.Salazar GonzalezR. M.JanesS.CostaF. T.AlibertiJ. (2013). Lipoxin A₄ and 15-epi-lipoxin A₄ protect against experimental cerebral malaria by inhibiting IL-12/IFN-γ in the brain. PloS one8 (4), e61882. 10.1371/journal.pone.0061882
108
SmithA. M.McCullersJ. A. (2014). Secondary bacterial infections in influenza virus infection pathogenesis. Curr. Top. Microbiol. Immunol.385, 327–356. 10.1007/82_2014_394
109
SuI. C.LeeK. L.LiuH. Y.ChuangH. C.ChenL. Y.LeeY. J. (2019). Severe community-acquired pneumonia due to Pseudomonas aeruginosa coinfection in an influenza A(H1N1)pdm09 patient. J. Microbiol. Immunol. Infect. = Wei mian yu gan ran za zhi52 (2), 365–366. 10.1016/j.jmii.2018.05.007
110
TamoutounourS.GuilliamsM.Montanana SanchisF.LiuH.TerhorstD.MalosseC.et al (2013). Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin. Immunity39 (5), 925–938. 10.1016/j.immuni.2013.10.004
111
TanA.SullenbargerB.PrakashR.McDanielJ. C. (2018). Supplementation with eicosapentaenoic acid and docosahexaenoic acid reduces high levels of circulating proinflammatory cytokines in aging adults: A randomized, controlled study. Prostagl. Leukot. Essent. Fat. acids132, 23–29. 10.1016/j.plefa.2018.03.010
112
TangL.YinZ.HuY.MeiH. (2020). Controlling cytokine storm is vital in COVID-19. Front. Immunol.11, 570993. 10.3389/fimmu.2020.570993
113
TangY.LiuJ.ZhangD.XuZ.JiJ.WenC. (2020). Cytokine storm in COVID-19: The current evidence and treatment strategies. Front. Immunol.11, 1708. 10.3389/fimmu.2020.01708
114
ThorntonJ. M.YinK. (2021). Role of specialized pro-resolving mediators in modifying host defense and decreasing bacterial virulence. Mol. (Basel, Switz.26 (22), 6970. 10.3390/molecules26226970
115
TitosE.RiusB.López-VicarioC.Alcaraz-QuilesJ.García-AlonsoV.LopategiA.et al (2016). Signaling and immunoresolving actions of resolvin D1 in inflamed human visceral adipose tissue. J. Immunol.197 (8), 3360–3370. 10.4049/jimmunol.1502522
116
von MoltkeJ.TrinidadN. J.MoayeriM.KintzerA. F.WangS. B.van RooijenN.et al (2012). Rapid induction of inflammatory lipid mediators by the inflammasome in vivo. Nature490 (7418), 107–111. 10.1038/nature11351
117
WalkerJ.DichterE.LacorteG.KernerD.SpurB.RodriguezA.et al (2011). Lipoxin a4 increases survival by decreasing systemic inflammation and bacterial load in sepsis. Shock (Augusta, Ga.)36 (4), 410–416. 10.1097/SHK.0b013e31822798c1
118
WangD.HuB.HuC.ZhuF.LiuX.ZhangJ.et al (2020). Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, China. JAMA323 (11), 1061–1069. 10.1001/jama.2020.1585
119
WangZ.LiS.HuangB. (2022). Alveolar macrophages: Achilles' heel of SARS-CoV-2 infection. Signal Transduct. Target. Ther.7 (1), 242. 10.1038/s41392-022-01106-8
120
WeillP.PlissonneauC.LegrandP.RiouxV.ThibaultR. (2020). May omega-3 fatty acid dietary supplementation help reduce severe complications in Covid-19 patients?Biochimie179, 275–280. 10.1016/j.biochi.2020.09.003
121
YangL.LiuS.LiuJ.ZhangZ.WanX.HuangB.et al (2020). COVID-19: Immunopathogenesis and immunotherapeutics. Signal Transduct. Target. Ther.5 (1), 128. 10.1038/s41392-020-00243-2
122
YangL.XieX.TuZ.FuJ.XuD.ZhouY. (2021). The signal pathways and treatment of cytokine storm in COVID-19. Signal Transduct. Target. Ther.6 (1), 255. 10.1038/s41392-021-00679-0
123
ZhangD.GuoR.LeiL.LiuH.WangY.WangY.et al (2021). Frontline science: COVID-19 infection induces readily detectable morphologic and inflammation-related phenotypic changes in peripheral blood monocytes. J. Leukoc. Biol.109 (1), 13–22. 10.1002/JLB.4HI0720-470R
124
ZhangJ.LiZ.FanM.JinW. (2022). Lipoxins in the nervous system: Brighter prospects for neuroprotection. Front. Pharmacol.13, 781889. 10.3389/fphar.2022.781889
125
ZhangJ.WangM.YeJ.LiuJ.XuY.WangZ.et al (2020). The anti-inflammatory mediator resolvin E1 protects mice against lipopolysaccharide-induced heart injury. Front. Pharmacol.11, 203. 10.3389/fphar.2020.00203
126
ZhaoD.YangB.YeC.ZhangS.LvX.ChenQ. (2021). Enteral nutrition ameliorates the symptoms of Crohn’s disease in mice via activating special pro-resolving mediators through innate lymphoid cells. Innate Immun.27 (7-8), 533–542. 10.1177/17534259211057038
127
ZhouF.YuT.DuR.FanG.LiuY.LiuZ.et al (2020). Clinical course and risk factors for mortality of adult inpatients with COVID-19 in wuhan, China: A retrospective cohort study. lancet395 (10229), 1054–1062. 10.1016/S0140-6736(20)30566-3
128
ZhouP.YangX. L.WangX. G.HuB.ZhangL.ZhangW.et al (2020). A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature579 (7798), 270–273. 10.1038/s41586-020-2012-7
Summary
Keywords
COVID-19, antimicrobial, cytokine storm, macrophages, lipid mediators
Citation
Kumar V, Yasmeen N, Chaudhary AA, Alawam AS, Al-Zharani M, Suliman Basher N, Harikrishnan S, Goud MD, Pandey A, Lakhawat SS and Sharma PK (2023) Specialized pro-resolving lipid mediators regulate inflammatory macrophages: A paradigm shift from antibiotics to immunotherapy for mitigating COVID-19 pandemic. Front. Mol. Biosci. 10:1104577. doi: 10.3389/fmolb.2023.1104577
Received
21 November 2022
Accepted
24 January 2023
Published
03 February 2023
Volume
10 - 2023
Edited by
Biswajit Mishra, Brown University, United States
Reviewed by
Toko Maehara, Iwate University, Japan
Vikram Sharma, Galgotias Educational Institutions, India
Updates
Copyright
© 2023 Kumar, Yasmeen, Chaudhary, Alawam, Al-Zharani, Suliman Basher, Harikrishnan, Goud, Pandey, Lakhawat and Sharma.
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.
*Correspondence: Vikram Kumar, vikramyadav05@gmail.com
† These authors have contributed equally to this work
This article was submitted to Molecular Diagnostics and Therapeutics, a section of the journal Frontiers in Molecular Biosciences
Disclaimer
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.