The role of macrophages in rosacea: implications for targeted therapies

Abstract

Introduction:

Rosacea, a widespread chronic skin condition, may be influenced by macrophages, key immune cells in the skin, although their exact role is not yet fully understood. This review delves into the function of macrophages, their potential contribution to rosacea pathogenesis, current treatments, and promising macrophage-targeted therapies. It concludes by identifying knowledge gaps and potential areas for future rosacea research.

Method:

Leveraging systematic and narrative literature review techniques, we conducted a comprehensive search of databases such as PubMed, Embase, and Web of Science. Utilizing keywords like “rosacea” and “macrophages”, we targeted English articles from the last 5 years (2018-2023). We manually checked reference lists of relevant articles for additional studies. We included only articles emphasizing macrophages’ role in rosacea and/or the development of related therapies and published within the specified timeframe.

Results:

The systematic search of electronic databases yielded a total of 4,263 articles. After applying the inclusion and exclusion criteria, 156 articles were selected for inclusion in this review. These articles included original research studies, review articles, and clinical trials that focused on the role of macrophages in rosacea and/or the development of macrophage-targeted therapies for the disease. The selected articles provided a comprehensive and up-to-date overview of the current state of research on macrophages in rosacea, including their function in the skin, the potential mechanisms through which they may contribute to rosacea pathogenesis, and the current treatments and therapies available for the disease. Additionally, the articles identified gaps in knowledge regarding the role of macrophages in rosacea and suggested potential areas for future research.

Conclusion:

This literature review emphasizes the important role that macrophages, vital immune cells in the skin, may play in the pathogenesis of rosacea, a common chronic inflammatory skin disorder. The selected studies suggest potential mechanisms by which these cells might contribute to rosacea progression, although these mechanisms are not yet fully understood. The studies also spotlight current rosacea treatments and illuminate the promising potential of new macrophage-focused therapies. Despite these insights, significant gaps persist in our understanding of the precise role of macrophages in rosacea. Future research in this area could provide further insights into the pathogenesis of rosacea and contribute to the development of more effective, targeted therapeutic strategies.

1 Introduction

Rosacea is a common chronic skin condition with redness, flushing, inflammation, and sometimes visible blood vessels or red, pus-filled bumps. Recent studies reveal variations within the disease spectrum (1–4). These phenotypes include erythematotelangiectatic rosacea (ETR) (3), characterized by persistent facial redness and visible blood vessels; papulopustular rosacea (PPR) (5), characterized by papules, pustules, and occasional nodules; and phymatous rosacea characterized by skin thickening and enlargement, predominantly affecting the nose (rhinophyma) (6). Identifying rosacea phenotypes is crucial for precise diagnosis and personalized management (7). Rosacea, usually appearing in adults over 30, has an unclear pathophysiology (8). Rosacea is influenced by genetics, environment, vascular factors, inflammation, and microbes (9). Rosacea’s prevalence in northern European populations and among those with a family history suggests a genetic predisposition (10). Rosacea can worsen due to environmental triggers like sunlight, heat, spicy foods, alcohol, stress, and certain cosmetics (11). Vascular issues in rosacea lead to facial blood vessel dysfunction, causing persistent redness, flushing, and visible vessels (12). Elevated Demodex folliculorum levels in rosacea sufferers suggest its involvement in the disease’s development (13). Rosacea’s pathophysiology involves skin barrier dysfunction and overproduction of proteins such as cathelicidin and kallikrein (14). These proteins cause inflammation, redness, and swelling and can trigger reactions to harmless bacteria (15). Rosacea treatment includes lifestyle changes, topical medication, oral antibiotics, and laser therapy (16). Topical treatments include metronidazole, azelaic acid, ivermectin, and brimonidine. Oral antibiotics like doxycycline are commonly used for their anti-inflammatory effects (17). Macrophages are essential immune cells that protect against pathogens in the skin and throughout the body (18). They ingest and digest pathogens through phagocytosis (19). Macrophages control inflammation, aid in healing and tissue repair, and remove damaged cells. Their role in rosacea is being studied, but their contribution to the disease is likely (20–22). Macrophages release mediators that cause redness, swelling, and pus-filled bumps in rosacea (23). Macrophages promote blood vessel growth, leading to persistent redness and visible vessels in rosacea (24). Macrophages respond to microbial stimuli, including the presence of D. folliculorum mites in rosacea patients, exacerbating inflammation (4). Abnormal immune response to environmental triggers may activate macrophages and contribute to rosacea (25). Research on macrophages in rosacea aims to uncover their role and develop new treatments. Understanding their function could reduce inflammation, improve patients’ quality of life, and shed light on related conditions. Further research is required to validate these findings and apply them in clinical practice.

2 Method and results

2.1 Method

The main databases used for the search included PubMed, Embase, and Web of Science. Our search strategy employed specific keywords related to “rosacea” and “macrophages”, with a particular emphasis on English language articles published within the timeframe of 2018 and 2023. Our research methodology extended to manual searches of reference lists from related articles to identify additional studies that could contribute valuable insights to our investigation. To ensure the integrity and relevance of our review, we followed strict inclusion and exclusion criteria, which were determined based on the focus of the article, its relevance to our study, the timeframe of publication, and the language in which the article was written. Our literature review process was the involvement of a multidisciplinary team composed of clinical physicians, dermatology researchers, and immunologists. This diverse team conducted the screening and evaluation process, ensuring a comprehensive and unbiased assessment of the articles based on our predefined criteria. The detailed process of our screening and evaluation, including the specific criteria used, is outlined in the Method section of our study. Flowchart could be referred (Figure 1). We believe that this rigorous and comprehensive methodology allowed us to capture a broad and current understanding of the relationship between macrophages and rosacea, contributing valuable insights to the existing body of knowledge.

Figure 1

2.2 Results

A systematic search yielded 4,263 articles, with 156 qualifying for inclusion post-criteria application. These articles, encompassing original studies, reviews, and clinical trials, highlighted macrophages’ role in rosacea and potential macrophage-targeted therapies. They provided an updated understanding of macrophages in rosacea, including their functions, contributions to pathogenesis, and current treatments. The articles also identified knowledge gaps and suggested future research areas.

3 The role of macrophages in skin and rosacea

Macrophages are immune cells that play a crucial role in maintaining tissue homeostasis and regulating the immune response in the skin (26). Macrophages have several crucial functions, including phagocytosis, debris clearance, antigen presentation, and cytokine secretion to recruit other immune cells to inflammation sites (27). In the skin, macrophages inhabit the dermis and epidermis, interacting with other cells like fibroblasts, keratinocytes, and dendritic cells to sustain skin health (28). In addition to aiding wound healing and tissue repair, macrophages resolve skin inflammation. In rosacea, they are thought to contribute to chronic inflammation and vascular dysfunction (29). Recent advancements underscore the pivotal role of macrophages in rosacea’s pathophysiology (30). Macrophages, acting as scavengers, clear body debris and microbes and are essential for wound healing, tissue repair, and resolving skin inflammation (31). In rosacea, macrophages seemingly contribute to the condition’s hallmark chronic inflammation and vascular dysfunction (32). In rosacea patients, researchers have discovered an overproduction of pro-inflammatory cytokines and angiogenic factors by macrophages (33), which promote inflammation and blood vessel formation. Also, these macrophages exhibit a hindered ability to transition from an inflammatory to a reparative state, extending the inflammatory response and intensifying tissue damage (34). This updated understanding of macrophages’ role in rosacea has unveiled potential therapies, like targeting macrophage function or specific cytokines (35), to alleviate the chronic inflammation and vascular dysfunction associated with the disease. Macrophages have multifaceted roles in rosacea, participating in maintaining skin health and wound healing and contributing to rosacea’s chronic inflammation and vascular dysfunction. A comprehensive overview of these functions and potential therapeutic implications is provided in Table 1.

3.1 Evidence for the involvement of macrophages in rosacea

Studies have shown elevated macrophage levels in the skin of individuals with rosacea, indicating their involvement in the condition (36). Carvedilol effectively treated rosacea by reducing inflammation, improving facial manifestations, and decreasing redness in patients after 4 and 6 months of treatment. It achieved this by inhibiting macrophage TLR2 expression, which may contribute to the vascular dysfunction associated with the disease (37). Studies have shown that macrophages in rosacea-affected skin express elevated levels of pro-inflammatory cytokines like IL-1β and TNF-α, surpassing those found in healthy skin (33). This heightened inflammatory response is thought to contribute to the persistent redness and inflammation seen in rosacea (38). The study examined facial biopsies from rosacea patients, revealing immune system activation and pro-inflammatory cell infiltration across all phenotypes. This prevalent chronic skin disorder presents with diverse signs on the central face, and a standardized system aims to aid diagnosis, research, and health-care communication, underscoring the significance of early identification and treatment to manage symptom progression (2). The updated classification system by the National Rosacea Society improves investigations, diagnosis, and treatment, particularly in specific demographics with a prevalence of 10% or higher, and more frequent diagnoses in women after the age of 30 (39). The efficacy and adverse event rates of various rosacea treatments are summarized in Supplementary Table 1 (40). Immunohistochemistry and flow cytometry techniques have shed light on the role of macrophages in rosacea by identifying and quantifying these cells in affected skin samples. This is crucial for understanding the immune response in the disease (41). Macrophages may contribute to rosacea pathogenesis through several potential mechanisms (42). One possibility is that they release pro-inflammatory cytokines that contribute to the persistent inflammation seen in the disease (43). These cytokines can trigger immune cell activation and attract more inflammatory cells to the skin, perpetuating an ongoing cycle of inflammation (44). Additionally, macrophages may play a role in the vascular dysfunction seen in rosacea (45). Macrophages are believed to play a role in both angiogenesis (formation of new blood vessels) and vasodilation (widening of existing vessels) in the skin (46), leading to the characteristic redness and flushing of rosacea (47). In rosacea, mast cell activation and the release of matrix metalloproteinases (MMPs) are additional potential mechanisms involved in the disease (48), which can break down the extracellular matrix and contribute to tissue damage (49). Gene expression analysis and functional assays unveil macrophages’ role in rosacea, with observed variations in gene expression profiles between healthy and affected skin samples (5, 50–53). Table 2 provides an example of such a comparison, highlighting differences in the expression of key genes involved in inflammation and macrophage function.

4 Progress and challenges in macrophage-targeted therapies for rosacea

Current treatments for rosacea typically focus on managing the symptoms of the disease rather than addressing its underlying cause (30). Metronidazole and doxycycline, in topical and oral forms, are commonly used to reduce skin inflammation and bacterial colonization (63). Topical azelaic acid and ivermectin have also been shown to be effective in reducing inflammation and improving the symptoms of rosacea (64). These treatments manage rosacea symptoms but do not address the underlying immune dysregulation and vascular dysfunction associated with the disease (30). Therefore, there is a need for novel, macrophage-targeted therapies that can address the root cause of rosacea (65). A potential macrophage-targeted therapy for rosacea involves using inhibitors that target pro-inflammatory cytokine production (66), such as IL-1β, by macrophages. Anakinra and canakinumab, IL-1β pathway inhibitors with a track record of reducing inflammation in other conditions, hold promise as potential treatments for rosacea (67). Another potential approach is targeting macrophage activation by environmental triggers like UV radiation (68). AhR-modulating drugs can reduce macrophage activation and inflammation in rosacea by targeting the skin’s response to environmental toxins (69). Tapinarof, an innovative topical treatment acting as an AhR agonist, holds promise in treating rosacea (70). This molecular mechanism focuses on the AhR, a ligand-activated transcription factor located in the cytoplasm (71). When tapinarof binds to AhR, it activates the receptor, leading to its translocation into the nucleus of skin cells (70, 72). This triggers the transcription of target genes that regulate inflammatory responses and strengthen the skin barrier function (73). Tapinarof has the potential to alleviate inflammatory responses and vascular dysregulation in rosacea (74, 75). Tapinarof’s potential effectiveness in improving skin barrier integrity may help alleviate rosacea symptoms (70, 76, 77). Referring to current sources is recommended for the latest information, as it may have evolved. In vitro assays and preclinical animal models can assess macrophage-targeted therapies’ efficacy and safety for rosacea (78), paving the way for the development of new treatments for this chronic skin disorder (79). Several clinical trials have investigated the efficacy of macrophage-targeted therapies for the treatment of rosacea (65). Table 3 summarizes trials with anakinra, canakinumab, and an AhR agonist, comparing current rosacea treatments. Topical and oral antibiotics reduce inflammation and bacterial colonization. Topical azelaic acid and ivermectin target skin turnover and Demodex mites, respectively. Topical steroids and oral non-steroidal anti-inflammatory drugs (NSAIDs) alleviate redness and inflammation but have potential side effects. Macrophage-targeted therapies show promise in addressing immune dysregulation and vascular dysfunction in rosacea. By targeting the pro-inflammatory cytokines and other molecules produced by macrophages (88), these therapies may be effective in reducing inflammation and improving the symptoms of rosacea (89). Targeted drug delivery systems or immunomodulatory nanoparticles can enhance the efficient and selective delivery of these therapies to the skin, minimizing potential side effects (90). However, there are also several limitations and challenges associated with macrophage-targeted therapies (91). Targeting macrophages specifically while avoiding impact on other skin cell types is challenging due to the complex interactions among immune cells in the skin’s immune response (92). Additionally, the potential for the development of drug resistance and the risk of side effects, such as immunosuppression, must be carefully considered (93). Table 4 outlines environmental triggers of macrophage activation in rosacea, including UV radiation, temperature changes, stress, alcohol, and spicy foods. These triggers induce inflammation, angiogenesis, nerve sensitivity, and macrophage activation, contributing to the disease’s progression. Furthermore, the cost and availability of these therapies may be a barrier to their widespread use (99). In vitro assays, animal models, and clinical trials are valuable for evaluating macrophage-targeted therapies in rosacea and addressing associated challenges (78). Recent progress in understanding the role of macrophages in rosacea has identified macrophage-targeted therapies as a promising treatment approach for the disease (78). However, developing effective macrophage-targeted therapies for rosacea is not without challenges (78). To address these challenges, various techniques have been used to assess the potential advantages and drawbacks of macrophage-targeted therapies for rosacea (78). In vitro assays evaluate treatment effects on macrophage function in a controlled environment, while preclinical animal models provide a whole organism setting for testing purposes (100). Clinical trials offer a valuable opportunity to assess the safety and efficacy of macrophage-targeted therapies in human patients (101).

4.1 Transition to a phenotype-based approach in rosacea diagnosis and management

An international group of dermatologists and ophthalmologists has unanimously endorsed a phenotype-based diagnostic and classification system for rosacea, a shift from the traditional approach of consensus-defined primary and secondary features. This new approach primarily identifies two phenotypes, persistent centrofacial erythema and phymatous changes, as independent diagnostic markers, whereas other features such as flushing, telangiectasia, and inflammatory lesions were not considered individually diagnostic. Moreover, the patient-focused transition from subtyping to phenotyping, backed by the ROSacea COnsensus (ROSCO) 2017 recommendations, aims to enhance personalized treatment strategies, taking into account the diverse range of rosacea manifestations and their impact on the patient’s quality of life. The panel also reevaluated treatment modalities based on recent advances in our understanding of rosacea’s pathophysiology, endorsing combination therapies, continued monitoring, and the use of a novel clinical tool, the Rosacea Tracker. These strategic changes aim to promote the utilization of the phenotypes approach in clinical practice and enhance rosacea patient management (47, 102, 103). These techniques reveal the mechanisms and benefits of macrophage-targeted therapies for rosacea. Anakinra and canakinumab showed reductions in inflammatory lesions and erythema in phase II trials, while preclinical studies on AhR agonists demonstrated decreased macrophage activation and cytokine production in vitro. Consult Table 5 for further details on these treatments and clinical trial results.

4.2 Advancements in understanding macrophage involvement in rosacea

Recent progress has improved our understanding of macrophages’ role in rosacea, a chronic skin condition marked by persistent redness and visible blood vessels (111). Various investigative techniques have been utilized to understand the intricate role of macrophages in the disease (121). One significant method used in this pursuit is immunohistochemistry (122). Immunohistochemistry allows scientists to visualize and assess the distribution and activation state of macrophages in rosacea-affected skin tissue samples using fluorescent or enzyme tags (123). By employing antibodies that target macrophage surface markers like CD68 or CD163, researchers can quantify and identify macrophages at different stages of rosacea progression (33). Flow cytometry, which uses laser light to assess cellular characteristics, is invaluable in determining the phenotype and functional attributes of macrophages (124). Flow cytometry assesses surface markers and cytokine expression to identify macrophage subsets, revealing their roles in triggering inflammation in rosacea (124, 125). Advanced molecular profiling techniques like single-cell RNA sequencing have improved our understanding of the diverse macrophage population (126). Single-cell RNA sequencing is a powerful tool that uncovers gene expression patterns associated with macrophage phenotypes, providing insights into their roles and interactions in rosacea (29, 127). These techniques aid in understanding how macrophages affect rosacea’s development and progression. They pave the way for targeted therapeutic interventions, revolutionizing management by addressing immune responses for more effective treatments in the future.

5 Future directions

Despite recent advances, significant knowledge gaps remain regarding the mechanisms by which macrophages contribute to rosacea (128). The environmental triggers that activate macrophages in rosacea, as well as the signaling pathways governing macrophage-mediated inflammation and angiogenesis, remain incompletely understood (129). The heterogeneity of skin macrophages and their interactions with other immune cells and structural cells like fibroblasts are still being investigated (130). Future research should address these knowledge gaps and develop new tools and techniques for studying skin macrophages (131). Advancements in single-cell sequencing, proteomics, and imaging technologies allow for detailed analysis of macrophage phenotypic and functional heterogeneity in the skin (132), as well as their interactions with other cell types. Identifying new macrophage-targeted therapies and improving rosacea treatments rely on these efforts. Recent progress in studying macrophages has paved the way for future research in rosacea (133). One key area of focus will be the development of new macrophage-targeted therapies that can address the underlying immune dysregulation and vascular dysfunction in the disease (134). This may involve identifying new molecular targets for therapy, as well as developing innovative drug delivery systems to improve the efficacy and safety of these therapies (135). Another important area of research will be the use of novel techniques to study macrophage function in the skin (136). Advances in imaging technologies, single-cell sequencing, and other high-throughput techniques may enable a more detailed analysis of macrophage heterogeneity and their interactions with other cells in the skin (137). Various techniques like flow cytometry, single-cell RNA sequencing, and in vitro assays, each with unique features and trade-offs, are employed to study macrophage function in rosacea. An overview of these techniques, including their advantages and limitations, is provided in Table 6. In addition, the use of preclinical animal models and clinical trials will be critical for evaluating the safety and efficacy of macrophage-targeted therapies and for identifying new molecular targets for therapy (150). Ultimately, the development of new macrophage-targeted therapies and a deeper understanding of macrophage function in rosacea may lead to improved treatments and outcomes for patients with this chronic skin disorder (65).

6 Conclusion

In conclusion, recent research has highlighted the potential role of macrophages in the pathogenesis of rosacea. Macrophages are important immune cells that play a critical role in regulating inflammation in the skin, and recent studies have suggested that their dysregulation may contribute to the chronic inflammation and vascular dysfunction seen in rosacea. While current treatments for rosacea focus on managing symptoms, the development of macrophage-targeted therapies represents a promising new approach to treating the underlying cause of the disease. Future research efforts will need to focus on addressing the gaps in our knowledge of macrophage function in rosacea, as well as developing new techniques and therapies to improve patient outcomes. The potential clinical implications of this research are significant, as the development of new macrophage-targeted therapies may lead to more effective treatments for rosacea, a common and chronic skin disorder that can significantly impact patients’ quality of life.

References

• 1

  RiveroALWhitfeldM. An update on the treatment of rosacea. Aust Prescr. (2018) 41:20. doi: 10.18773/austprescr.2018.004

  • CrossRef
  • Google Scholar

• 2

  GalloRLGransteinRDKangSMannisMSteinhoffMTanJet al. Standard classification and pathophysiology of rosacea: The 2017 update by the National Rosacea Society Expert Committee. J Am Acad Dermatol (2018) 78:148–55. doi: 10.1016/j.jaad.2017.08.037

  • CrossRef
  • Google Scholar

• 3

  SearleTAl-NiaimiFAliFR. Rosacea and the cardiovascular system. (2020) 19:2182–7. doi: 10.1111/jocd.13587

  • CrossRef
  • Google Scholar

• 4

  FortonFM. Rosacea, an infectious disease: why rosacea with papulopustules should be considered a demodicosis. A narrative review. J Eur Acad Dermatol Venereol (2022) 36:987–1002. doi: 10.1111/jdv.18049

  • CrossRef
  • Google Scholar

• 5

  LiuFChenMHuangCXiaoWGaoSJianDet al. Keratinocyte-immune cell crosstalk in a STAT1-mediated pathway: novel insights into rosacea pathogenesis. Front Immunol (2021) 12:674871. doi: 10.3389/fimmu.2021.674871

  • CrossRef
  • Google Scholar

• 6

  DayritJF. Rosacea. In: Skin Diseases in Females. Springer (2022). p. 137–51.

  • Google Scholar

• 7

  MaruthappuTTaylorMJCDermatologyE. Acne and rosacea in skin of colour. Clin Exp Dermatol (2022) 47:259–63. doi: 10.1111/ced.14994

  • CrossRef
  • Google Scholar

• 8

  AgarwalP. Acne, rosacea, and similar disorders. In: Concise Dermatology. CRC Press (2021). p. 134–49.

  • Google Scholar

• 9

  HolmesADSpoendlinJChienALBaldwinHChangALS. Evidence-based update on rosacea comorbidities and their common physiologic pathways. J Am Acad Dermatol (2018) 78:156–66. doi: 10.1016/j.jaad.2017.07.055

  • CrossRef
  • Google Scholar

• 10

  AwosikaOOussedikEJDC. Genetic predisposition to rosacea. Dermatol Clin (2018) 36(2):87–92. doi: 10.1016/j.det.2017.11.002

  • CrossRef
  • Google Scholar

• 11

  Morgado-CarrascoDGrangerCTrullasCPiquero-CasalsJ. Impact of ultraviolet radiation and exposome on rosacea: Key role of photoprotection in optimizing treatment. J Cosmet Dermatol (2021) 20(11):3415–21. doi: 10.1111/jocd.14020

  • CrossRef
  • Google Scholar

• 12

  RastogiVSinghDMazzaJJParajuliDYaleSH. Flushing disorders associated with gastrointestinal symptoms: part 1, neuroendocrine tumors, mast cell disorders and hyperbasophila. Clin Med Res (2018) 16(1-2):16–28. doi: 10.3121/cmr.2017.1379a

  • CrossRef
  • Google Scholar

• 13

  Lugović-MihićLŠpiljakBBlagecTDelaš AždajićMFranceschiNGašićAet al. Factors participating in the occurrence of inflammation of the lips (Cheilitis) and perioral skin. Cosmetics (2023) 10:9. doi: 10.3390/cosmetics10010009

  • CrossRef
  • Google Scholar

• 14

  DengZChenMLiuYXuSOuyangYShiWet al. A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea. EMBO Mol Med (2021) 13(5): e13560. doi: 10.15252/emmm.202013560

  • CrossRef
  • Google Scholar

• 15

  EfferthTOeschF. The immunosuppressive activity of artemisinin-type drugs towards inflammatory and autoimmune diseases. Med Res Rev (2021) 41(6):3023–61. doi: 10.1002/med.21842

  • CrossRef
  • Google Scholar

• 16

  WladisEJAdamAP. Treatment of ocular rosacea. Surv Ophthalmol (2018) 63(3):340–6. doi: 10.1016/j.survophthal.2017.07.005

  • CrossRef
  • Google Scholar

• 17

  BonamigoRRBertoliniWde OliveiraFBDornellesSIT. Rosacea. In: Dermatology in Public Health Environments: A Comprehensive Textbook. Springer (2023). p. 603–20.

  • Google Scholar

• 18

  PengGFadeelB. Understanding the bidirectional interactions between two-dimensional materials, microorganisms, and the immune system. Adv Drug Deliv Rev (2022) 188:114422. doi: 10.1016/j.addr.2022.114422

  • CrossRef
  • Google Scholar

• 19

  MinasyanH. Phagocytosis and oxycytosis: two arms of human innate immunity. Immunol Res (2018) 66(2):271–80. doi: 10.1007/s12026-018-8988-5

  • CrossRef
  • Google Scholar

• 20

  MartinKEGarcíaA. (2021) 133:4–16.

  • Google Scholar

• 21

  GuerrieroJ. Macrophages: their untold story in T cell activation and function. Int Rev Cell Mol Biol (2019) 342:73–93doi: 10.1016/bs.ircmb.2018.07.001.

  • CrossRef
  • Google Scholar

• 22

  WangF-YChiC-C. Rosacea, germs, and bowels: a review on gastrointestinal comorbidities and gut–skin axis of rosacea. Adv Ther (2021) 38(3):1415–24. doi: 10.1007/s12325-021-01624-x

  • CrossRef
  • Google Scholar

• 23

  AndeSNBodakheAABakalRLChandewarAV. How do acute and chronic inflammatory skin diseases arise? A Brief Rev (2022).

  • Google Scholar

• 24

  Rodrigues-BrazDZhaoMYesilirmakNAractingiSBehar-CohenFBourgesJL. Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models. Mol Vis (2021) 27:323.

  • Google Scholar

• 25

  WangLWangYJHaoDWenXDuDHeGet al. The theranostics role of mast cells in the pathophysiology of rosacea. Front Med (Lausanne) (2020) 6:324. doi: 10.3389/fmed.2019.00324

  • CrossRef
  • Google Scholar

• 26

  Diaz-JimenezDKolbJPCidlowskiJA. Glucocorticoids as regulators of macrophage-mediated tissue homeostasis. Front Immunol (2021) 12:669891. doi: 10.3389/fimmu.2021.669891

  • CrossRef
  • Google Scholar

• 27

  ZhuWSuJ. Immune functions of phagocytic blood cells in teleost. Rev Aquac (2022) 14:630–46. doi: 10.1111/raq.12616

  • CrossRef
  • Google Scholar

• 28

  SumpterTLBalmertSCKaplanDH. Cutaneous immune responses mediated by dendritic cells and mast cells. JCI Insight (2019) 4(1):e123947. doi: 10.1172/jci.insight.123947

  • CrossRef
  • Google Scholar

• 29

  GuimarãesGRAlmeidaPPde Oliveira SantosLRodriguesLPde CarvalhoJLBoroniM. Hallmarks of aging in macrophages: consequences to skin inflammaging. Cells (2021) 10(6):1323.doi: 10.3390/cells10061323

  • CrossRef
  • Google Scholar

• 30

  DelansKKellyKFeldmanSR. Treatment strategies, including antibiotics, to target the immune component of rosacea. Expert Rev Clin Immunol (2022) 18(12):1239–51. doi: 10.1080/1744666X.2022.2128334

  • CrossRef
  • Google Scholar

• 31

  HuangCDongLZhaoBLuYHuangSYuanZet al. Anti-inflammatory hydrogel dressings and skin wound healing. Clin Transl Med (2022) 12(11): e1094. doi: 10.1002/ctm2.1094

  • CrossRef
  • Google Scholar

• 32

  MeliVSVeerasubramanianPKAtchaHReitzZDowningTLLiuWF. Biophysical regulation of macrophages in health and disease. J Leukoc Biol (2019) 106:283–99. doi: 10.1002/JLB.MR0318-126R

  • CrossRef
  • Google Scholar

• 33

  SunQHuSLouZGaoJ. The macrophage polarization in inflammatory dermatosis and its potential drug candidates. Biomed Pharmacother (2023) 161:114469. doi: 10.1016/j.biopha.2023.114469

  • CrossRef
  • Google Scholar

• 34

  Irizarry-CaroRAMcDanielMMOvercastGRJainVGTroutmanTDPasareC. TLR signaling adapter BCAP regulates inflammatory to reparatory macrophage transition by promoting histone lactylation. Proc Natl Acad Sci U S A (2020) 117(48):30628–38. doi: 10.1073/pnas.2009778117

  • CrossRef
  • Google Scholar

• 35

  MookherjeeNAndersonMAHaagsmanHPDavidsonD. Antimicrobial host defence peptides: functions and clinical potential. Nat Rev Drug Discov (2020) 19(5):311–32. doi: 10.1038/s41573-019-0058-8

  • CrossRef
  • Google Scholar

• 36

  ZhangJJiangPShengLLiuYLiuYLiMet al. A novel mechanism of carvedilol efficacy for rosacea treatment: toll-like receptor 2 inhibition in macrophages. Front Immunol (2021) 12:609615. doi: 10.3389/fimmu.2021.609615

  • CrossRef
  • Google Scholar

• 37

  Silveira RossiJLBarbalhoSMReverete de AraujoRBecharaMDSloanKPSloanLA. Metabolic syndrome and cardiovascular diseases: Going beyond traditional risk factors. Diabetes Metab Res Rev (2022) 38(3): e3502doi: 10.1002/dmrr.3502.

  • CrossRef
  • Google Scholar

• 38

  MarsonJWBaldwinHE. Rosacea: a wholistic review and update from pathogenesis to diagnosis and therapy. Int J Dermatol (2020) 59(6):e175–82. doi: 10.1111/ijd.14757

  • CrossRef
  • Google Scholar

• 39

  WilkinJDahlMDetmarMDrakeLFeinsteinAOdomRet al. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol (2002) 46:584–7. doi: 10.1067/mjd.2002.120625

  • CrossRef
  • Google Scholar

• 40

  KangCNShahMTanJ. Rosacea: an update in diagnosis, classification and management. Skin Ther Lett (2021) 26(4):1–8.

  • Google Scholar

• 41

  Luque-MartinRAngellDCKalxdorfMBernardSThompsonWEberlHCet al. IFN-γ drives human monocyte differentiation into highly proinflammatory macrophages that resemble a phenotype relevant to psoriasis. J Immunol (2021) 207(2):555–68. doi: 10.4049/jimmunol.2001310

  • CrossRef
  • Google Scholar

• 42

  ZhangHZhangYLiYWangYYanSXuSet al. Bioinformatics and network pharmacology identify the therapeutic role and potential mechanism of melatonin in AD and Rosacea. Front Immunol (2021) 12:756550. doi: 10.3389/fimmu.2021.756550

  • CrossRef
  • Google Scholar

• 43

  RossRContiP. COVID-19 induced by SARS-CoV-2 causes Kawasaki-like disease in children: Role of pro-inflammatory and anti-inflammatory cytokines. Front Immunol (2020) 34:767–73doi: 10.23812/EDITORIAL-RONCONI-E-59.

  • CrossRef
  • Google Scholar

• 44

  NiXLaiY. Keratinocyte: A trigger or an executor of psoriasis? J Leukoc Biol (2020) 108(2):485–91. doi: 10.1002/JLB.5MR0120-439R

  • CrossRef
  • Google Scholar

• 45

  LiuZZhangJJiangPYinZLiuYLiuYet al. Paeoniflorin inhibits the macrophage-related rosacea-like inflammatory reaction through the suppressor of cytokine signaling 3-apoptosis signal-regulating kinase 1-p38 pathway. Medicine (Baltimore) (2021) 100(3):e23986. doi: 10.1097/MD.0000000000023986

  • CrossRef
  • Google Scholar

• 46

  LeeHJHongYJKimM. Angiogenesis in chronic inflammatory skin disorders. (2021) 22:12035. doi: 10.3390/ijms222112035

  • CrossRef
  • Google Scholar

• 47

  van ZuurenEJArentsBWMvan der LindenMMDVermeulenSFedorowiczZTanJ. Rosacea: new concepts in classification and treatment. Am J Clin Dermatol (2021) 22:457–65. doi: 10.1007/s40257-021-00595-7

  • CrossRef
  • Google Scholar

• 48

  JiangPLiuYZhangJLiuYLiMTaoMet al. Mast cell stabilization: new mechanism underlying the therapeutic effect of intense pulsed light on rosacea. Inflamm Res (2023) 72(1):75–88. doi: 10.1007/s00011-022-01635-6

  • CrossRef
  • Google Scholar

• 49

  TheocharisADManouDKaramanosNK. The extracellular matrix as a multitasking player in disease. FEBS J (2019) 286(15):2830–69. doi: 10.1111/febs.14818

  • CrossRef
  • Google Scholar

• 50

  YangLShouY-HYangY-SXuJ-H. Elucidating the immune infiltration in acne and its comparison with rosacea by integrated bioinformatics analysis. PLoS One (2021) 16(3): e0248650. doi: 10.1371/journal.pone.0248650

  • CrossRef
  • Google Scholar

• 51

  DullKLénártKDajnokiZPóliskaSUchiyamaEHendrikZet al. Barrier function-related genes and proteins have an altered expression in acne-involved skin. J Eur Acad Dermatol Venereol (2023) 37(7):1415–25. doi: 10.1111/jdv.19062

  • CrossRef
  • Google Scholar

• 52

  LiuTDengZXieHChenMXuSPengQet al. ADAMDEC1 promotes skin inflammation in rosacea via modulating the polarization of M1 macrophages. Biochem Biophys Res Commun (2020) 521:64–71. doi: 10.1016/j.bbrc.2019.10.073

  • CrossRef
  • Google Scholar

• 53

  XiaoWChenMPengQShaKLiuTXiaJet al. Lithocholic acid promotes rosacea-like skin inflammation via G protein-coupled bile acid receptor. Biochim Biophys Acta Mol Basis Dis (2022) 1868(12):166563. doi: 10.1016/j.bbadis.2022

  • CrossRef
  • Google Scholar

• 54

  GoldLSDel RossoJQKircikLBhatiaNDHooperDNahmWKet al. Minocycline 1.5% foam for the topical treatment of moderate to severe papulopustular rosacea: results of 2 phase 3, randomized, clinical trials. J Am Acad Dermatol (2020) 82(5):1166–73.

  • Google Scholar

• 55

  Rosacea. In: Australian Journal for General Practitioners, vol. 46. p. 277–81.

  • Google Scholar

• 56

  Husein-ElAhmedHSteinhoffM. Evaluation of the efficacy of subantimicrobial dose doxycycline in rosacea: a systematic review of clinical trials and meta-analysis. J Dtsch Dermatol Ges (2021) 19(1):7–17. doi: 10.1111/ddg.14247

  • CrossRef
  • Google Scholar

• 57

  Del RossoJQTanghettiEWebsterGStein GoldLThiboutotDGalloRL. Update on the management of rosacea from the American acne & Rosacea Society (AARS). J Clin Aesthetic Dermatol (2020) 13(6 Suppl):S17–s24.

  • Google Scholar

• 58

  van ZuurenEJFedorowiczZTanJvan der LindenMMDArentsBWMCarterBet al. Interventions for rosacea based on the phenotype approach: an updated systematic review including GRADE assessments. Br J Dermatol (2019) 181:65–79. doi: 10.1111/bjd.17590

  • CrossRef
  • Google Scholar

• 59

  SearleTAliFRCarolidesSAl-NiaimiF. Rosacea and Diet: What is New in 2021? J Clin Aesthet Dermatol (2021) 14(12):49–54.

  • Google Scholar

• 60

  EbbelaarCCFVenemaAWVan DijkMR. Topical Ivermectin in the treatment of Papulopustular Rosacea: A systematic review of evidence and clinical guideline recommendations. Dermatol Ther (2018) 8:379–87. doi: 10.1007/s13555-018-0249-y

  • CrossRef
  • Google Scholar

• 61

  ÁvilaMYMartínez-PulgarínDFMadridC.R.J.C.L.EyeA. Topical ivermectin-metronidazole gel therapy in the treatment of blepharitis caused by Demodex spp.: a randomized clinical trial. Cont Lens Anterior Eye (2021) 44(3):101326. doi: 10.1016/j.clae.2020.04.011

  • CrossRef
  • Google Scholar

• 62

  SchallerMKeményLHavlickovaBJacksonJMAmbroziakMLyndeCet al. A randomized phase 3b/4 study to evaluate concomitant use of topical ivermectin 1% cream and doxycycline 40-mg modified-release capsules, versus topical ivermectin 1% cream and placebo in the treatment of severe rosacea. J Am Acad Dermatol (2020) 82:336–43. doi: 10.1016/j.jaad.2019.05.063

  • CrossRef
  • Google Scholar

• 63

  FukutaYChuaHPheKLee PoythressEBrownCA. Infectious diseases management in wound care settings: common causative organisms and frequently prescribed antibiotics. Adv Skin Wound Care (2022) 35(10):535–43. doi: 10.1097/01.ASW.0000855744.86686.ea

  • CrossRef
  • Google Scholar

• 64

  SharmaAKroumpouzosGKassirMGaladariHGorenAGrabbeSet al. Rosacea management: a comprehensive review. J Cosmet Dermatol (2022) 21(5):1895–90410.1111/jocd.14816.

  • CrossRef
  • Google Scholar

• 65

  JainAKJainSAbourehabMAMehtaPKesharwaniP. An insight on topically applied formulations for management of various skin disorders. J Biomater Sci Polym Ed (2022) 33(18):2406–32. doi: 10.1080/09205063.2022.2103625

  • CrossRef
  • Google Scholar

• 66

  QuaresmaJAS. Organization of the skin immune system and compartmentalized immune responses in infectious diseases. Clin Microbiol Rev (2019) 32(4):e00034–00018. doi: 10.1128/CMR.00034-18

  • CrossRef
  • Google Scholar

• 67

  FergusonPJde JesusAAGoldbach-ManskyR. Autoinflammatory diseases affecting bone and joints, and autoinflammatory interferonopathies. In: Stiehm’s Immune Deficiencies. Elsevier (2020). p. 685–720.

  • Google Scholar

• 68

  WangMChararehPLeiXZhongJL. Autophagy: multiple mechanisms to protect skin from ultraviolet radiation-driven photoaging. Oxid Med Cell Longev (2019) 2019:8135985. doi: 10.1155/2019/8135985

  • CrossRef
  • Google Scholar

• 69

  PasseronTZouboulisCCTanJAndersenMLKattaRLyuXet al. Adult skin acute stress responses to short-term environmental and internal aggression from exposome factors. J Eur Acad Dermatol Venereol (2021) 35(10):1963–75. doi: 10.1111/jdv.17432

  • CrossRef
  • Google Scholar

• 70

  PaikSJKimDJJungSK. Preventive effect of pharmaceutical phytochemicals targeting the Src family of protein tyrosine kinases and aryl hydrocarbon receptor on environmental stress-induced skin disease. Int J Mol Sci (2023) 24:5953. doi: 10.3390/ijms24065953

  • CrossRef
  • Google Scholar

• 71

  XiaTFuSYangRYangK. Advances in the study of macrophage polarization in inflammatory immune skin diseases. Authorea (2023). doi: 10.22541/au.168369484.44857588/v1

  • CrossRef
  • Google Scholar

• 72

  NapolitanoMFabbrociniGMartoraFPiconeVMorelliPPatrunoC. Role of aryl hydrocarbon receptor activation in inflammatory chronic skin diseases. Cells (2021) 10(11):3559. doi: 10.3390/cells10123559

  • CrossRef
  • Google Scholar

• 73

  Fernández-GallegoNSánchez-MadridFCibrianDJC. Role of AHR ligands in skin homeostasis and cutaneous inflammation. Cells (2021) 10(11):3176. doi: 10.3390/cells10113176.

  • CrossRef
  • Google Scholar

• 74

  MooneyN. Harvard Medical School. (2022).

  • Google Scholar

• 75

  BissonnetteRGoldLSRubensteinDSTallmanAMArmstrongA. Tapinarof in the treatment of psoriasis: A review of the unique mechanism of action of a novel therapeutic aryl hydrocarbon receptor–modulating agent. J Am Acad Dermatol (2021) 84(4):1059–67. doi: 10.1016/j.jaad.2020.10.085

  • CrossRef
  • Google Scholar

• 76

  FabbrociniGMonteilCBCarballidoF. A cream containing the sap of oat plantlets and mandarin extract soothes the symptoms of rosacea and improves the quality of life of patients. J Eur Acad Dermatol Venereol (2022) 36:3–11. doi: 10.1111/jdv.18201

  • CrossRef
  • Google Scholar

• 77

  YosipovitchGMiseryLProkschEMetzMStänderSSchmelzM. Skin barrier damage and itch: review of mechanisms, topical management and future directions. Acta Derm Venereol (2019) 99(13):1201–9. doi: 10.2340/00015555-3296

  • CrossRef
  • Google Scholar

• 78

  JainKAhmadJ. Nanotheranostics for Treatment and Diagnosis of Infectious Diseases. Academic Press (2022).

  • Google Scholar

• 79

  Di ColaIRuscittiPGiacomelliRCiprianiP. The pathogenic role of interferons in the hyperinflammatory response on adult-onset Still’s disease and macrophage activation syndrome: paving the way towards new therapeutic targets. J. Clin. Med (2021) 10:1164. doi: 10.3390/jcm10061164

  • CrossRef
  • Google Scholar

• 80

  CasasCPaulCLahfaMLivideanuBLejeuneOAlvarez-GeorgesSet al. Quantification of Demodex folliculorum by PCR in rosacea and its relationship to skin innate immune activation. Exp Dermatol (2012) 21(12):906–10. doi: 10.1111/exd.12030

  • CrossRef
  • Google Scholar

• 81

  SearleTAliFRCarolidesSAl-NiaimiF. Rosacea and the gastrointestinal system. Australas J Dermatol (2020) 61(4):307–11. doi: 10.1111/ajd.13401

  • CrossRef
  • Google Scholar

• 82

  GaoCGeLChenDZhangMZhaoLLiuWet al. Increased frequency of circulating classical monocytes in patients with Rosacea. Clin Cosmetic Investigational Dermatol (2021) 14:1629–36. doi: 10.2147/CCID.S336194

  • CrossRef
  • Google Scholar

• 83

  LiMTaoMZhangYPanRGuDXuY. Neurogenic rosacea could be a small fiber neuropathy. Front Pain Res (Lausanne) (2023) 4:1122134. doi: 10.3389/fpain.2023.1122134

  • CrossRef
  • Google Scholar

• 84

  KimJKimKJM. Elucidating the potential pharmaceutical mechanism of Gyejibokryeong-hwan on rosacea using network analysis. Medicine (Baltimore) (2023) 102(9):e33023. doi: 10.1097/MD.0000000000033023

  • CrossRef
  • Google Scholar

• 85

  MutoYWangZVanderbergheMTwoAGalloRLDi NardoA. Mast cells are key mediators of cathelicidin-initiated skin inflammation in rosacea. J Invest Dermatol (2014) 134(11):2728–36. doi: 10.1038/jid.2014.222

  • CrossRef
  • Google Scholar

• 86

  ZhouLZhaoHZhaoHMengXZhaoZXieHet al. GBP5 exacerbates rosacea-like skin inflammation by skewing macrophage polarization towards M1 phenotype through the NF-κB signalling pathway. J Eur Acad Dermatol Venereol: JEADV (2023) 37:796–809. doi: 10.1111/jdv.18725

  • CrossRef
  • Google Scholar

• 87

  PengQShaKLiuYChenMXuSHongfu XieHet al. mTORC1-mediated angiogenesis is required for the development of Rosacea. Front Cell Dev Biol (2021) 9:751785. doi: 10.3389/fcell.2021.751785

  • CrossRef
  • Google Scholar

• 88

  SioutiEAndreakosE. The many facets of macrophages in rheumatoid arthritis. Biochem Pharmacol (2019) 165:152–69. doi: 10.1016/j.bcp.2019.03.029

  • CrossRef
  • Google Scholar

• 89

  BarbarinoSCBucayVWCohenJLGoldMH. Integrative skincare trial of intense pulsed light followed by the phyto-corrective mask, phyto-corrective gel, and resveratrol BE for decreasing post-procedure downtime and improving procedure outcomes in patients with rosacea. J Cosmet Dermatol (2022) 21(9):3759–67. doi: 10.1111/jocd.15189

  • CrossRef
  • Google Scholar

• 90

  SahuTRatreYKChauhanSBhaskarLVKSNairMPVermaHK. Nanotechnology based drug delivery system: Current strategies and emerging therapeutic potential for medical science. Journal of Drug Delivery Science and Technology (2021) 63:102487. doi: 10.1016/j.jddst.2021.102487

  • CrossRef
  • Google Scholar

• 91

  ZhaoY-DMuhetaerjiangMAnHWFangXZhaoYWangH. Nanomedicine enables spatiotemporally regulating macrophage-based cancer immunotherapy. Biomaterials (2021) 268:120552. doi: 10.1016/j.biomaterials.2020.120552

  • CrossRef
  • Google Scholar

• 92

  WahabSGhazwaniMHaniUHakamiARAlmehiziaAAAhmadWet al. Nanomaterials-based novel immune strategies in clinical translation for cancer therapy. Molecules (2023) 28(3):1216. doi: 10.3390/molecules28031216

  • CrossRef
  • Google Scholar

• 93

  KothariDPatelSKimS-K. Probiotic supplements might not be universally-effective and safe: A review. Biomed Pharmacother (2019) 111:537–47. doi: 10.1016/j.biopha.2018.12.104

  • CrossRef
  • Google Scholar

• 94

  Goldbach-ManskyRShroffSDWilsonMSnyderCPlehnSBarhamBet al. A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 Trap) in patients with familial cold autoinflammatory syndrome. Arthritis Rheumatism (2008) 58(8):2432–42. doi: 10.1002/art.23620

  • CrossRef
  • Google Scholar

• 95

  SáDFesta NetoC. Inflammasomes and dermatology. Anais Brasileiros Dermatol (2016) 91.

  • Google Scholar

• 96

  ArnoldDDYalamanogluABoymanO. Systematic review of safety and efficacy of IL-1-targeted biologics in treating immune-mediated disorders. Front Immunol (2022) 13:888392. doi: 10.3389/fimmu.2022.888392

  • CrossRef
  • Google Scholar

• 97

  MarghoobAAHighWAJDM. Acne and Rosacea Update: Maui Derm 2019 Highlights. (2019).

  • Google Scholar

• 98

  SunYChenLHWangHXZhuPYJiangSBQiRQet al. Activation of aryl hydrocarbon receptor ameliorates rosacea-like eruptions in mice and suppresses the TLR signaling pathway in LL-37-induced HaCaT cells. Toxicol Appl Pharmacol (2022) 451:116189. doi: 10.1016/j.taap.2022.116189

  • CrossRef
  • Google Scholar

• 99

  RafiqSHackettCSBrentjensR. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat Rev Clin Oncol (2020) 17(3):147–67. doi: 10.1038/s41571-019-0297-y

  • CrossRef
  • Google Scholar

• 100

  MoviaDPrina-MelloA. Preclinical development of orally inhaled drugs (OIDs)—are animal models predictive or shall we move towards in vitro non-animal models? Animals (Basel) (2020) 10(8):1259. doi: 10.3390/ani10081259

  • CrossRef
  • Google Scholar

• 101

  WangSYangYMaPHuangHTangQMiaoHet al. Landscape and perspectives of macrophage targeted cancer therapy in clinical trials. Mol Ther Oncolytic (2022) 24:799–813. doi: 10.1016/j.omto.2022.02.019

  • CrossRef
  • Google Scholar

• 102

  TanJAlmeidaLMBewleyACribierBDlovaNCGalloRet al. Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel. Br J Dermatol (2017) 176(2):431–8. doi: 10.1111/bjd.15122

  • CrossRef
  • Google Scholar

• 103

  SchallerMAlmeidaLMCBewleyACribierBDel RossoJDlovaNCet al. Recommendations for rosacea diagnosis, classification and management: update from the global ROSacea COnsensus 2019 panel. Br J Dermatol (2020) 182:1269–76. doi: 10.1111/bjd.18420

  • CrossRef
  • Google Scholar

• 104

  MelnikB. C. Endoplasmic reticulum stress: key promoter of rosacea pathogenesis. Exp Dermatol (2014) 23(12):868–73. doi: 10.1111/exd.12517

  • CrossRef
  • Google Scholar

• 105

  OhSSonMParkJKangDByunKJM. Radiofrequency irradiation modulates TRPV1-related burning sensation in rosacea. Molecules (2021) 26(5):1424. doi: 10.3390/molecules26051424

  • CrossRef
  • Google Scholar

• 106

  ChenMDengZHuangYLiJ. Prevalence and risk factors of anxiety and depression in rosacea patients: a cross-sectional study in China. Front Psychiatry (2021) 12:659171. doi: 10.3389/fpsyt.2021.659171

  • CrossRef
  • Google Scholar

• 107

  KreidelMKJhaveriM. Introduction to essential oils and essential oil processing. (2021), 99–122. doi: 10.1007/978-3-030-58954-7_5

  • CrossRef
  • Google Scholar

• 108

  KimJAhamedAChenKLebigEGPetrosBSaeedSet al. Skin microbiota and its role in health and disease with an emphasis on wound healing and chronic wound development. In: Microbiome, Immunity, Digestive Health and Nutrition. Elsevier (2022). p. 297–311. doi: 10.1016/B978-0-12-822238-6.00027-3

  • CrossRef
  • Google Scholar

• 109

  FortonFM. The pathogenic role of Demodex mites in Rosacea: a potential therapeutic target already in erythematotelangiectatic Rosacea? Dermatol Ther (Heidelb) (2020) 10(6):1229–53. doi: 10.1007/s13555-020-00458-9

  • CrossRef
  • Google Scholar

• 110

  ShaxnozaMYelenaYSevaraM. Determination of the level of some indicators of inflammation in patients with Rosacea. European Journal of Modern Medicine and Practice (2022) 2:38–42.

  • Google Scholar

• 111

  MahantiB. A clinical overview on acuteness of rosacea. (2020).

  • Google Scholar

• 112

  JabbehdariSMemarOMCaughlinBDjalilianAR. Update on the pathogenesis and management of ocular rosacea: an interdisciplinary review. Eur J Ophthalmol (2021) 31(1):22–33. doi: 10.1177/1120672120937252

  • CrossRef
  • Google Scholar

• 113

  PatelNVGuptaNShettyR. Preferred practice patterns and review on rosacea. Indian J Ophthalmol (2023) 71:1382–90.

  • Google Scholar

• 114

  WienholtzNKFEgebergAThyssenJPJR. Rosacea and cardiovascular comorbidities. Rosacea (2020), 105–12. doi: 10.1007/978-3-030-52097-7_10

  • CrossRef
  • Google Scholar

• 115

  AliaEFengH. Rosacea pathogenesis, common triggers, and dietary role: the cause, the trigger, and the positive effects of different foods. Clinics Dermatol (2022) 40:122–7. doi: 10.1016/j.clindermatol.2021.10.004

  • CrossRef
  • Google Scholar

• 116

  KochKDlovaN. Skin care in sensitive skin of Rosacea. (2019).

  • Google Scholar

• 117

  NowickaDChilickaKDzieńdziora-UrbińskaISzygułaR. Skincare in Rosacea from the cosmetologist’s perspective: A narrative review. J Clin Med (2022) 12(1):115. doi: 10.3390/jcm12010115

  • CrossRef
  • Google Scholar

• 118

  SantoroFLachmannN. An open-label, intra-individual study to evaluate a regimen of three cosmetic products combined with medical treatment of Rosacea: cutaneous tolerability and effect on hydration. Dermatol Ther (Heidelb) (2019) 9:775–84. doi: 10.1007/s13555-019-00331-4

  • CrossRef
  • Google Scholar

• 119

  YamasakiKMiyachiY. Perspectives on rosacea patient characteristics and quality of life using baseline data from a phase 3 clinical study conducted in Japan. J Dermatol (2022) 49(12):1221–7. doi: 10.1111/1346-8138.16596

  • CrossRef
  • Google Scholar

• 120

  CafNÖzkök AkbulutTCanMMSarıMAtsüANTürkoğluZ. Evaluation of subclinical atherosclerosis in rosacea patients by flow-mediated dilatation method. J Cosmet Dermatol (2023) 22:1001–10. doi: 10.1111/jocd.15492

  • CrossRef
  • Google Scholar

• 121

  AlfordMABaquirBSantanaFLHaneyEFHancockRE. Cathelicidin host defense peptides and inflammatory signaling: Striking a balance. Front Microbiol (2020) 11:1902. doi: 10.3389/fmicb.2020.01902

  • CrossRef
  • Google Scholar

• 122

  CribierB. Rosacea: Treatment targets based on new physiopathology data. In: Annales de Dermatologie et de Vénéréologie, vol. 149. Elsevier (2022). p. 99–107.

  • Google Scholar

• 123

  HauckSet al. Collagen/hyaluronan based hydrogels releasing sulfated hyaluronan improve dermal wound healing in diabetic mice via reducing inflammatory macrophage activity. Bioact Mater (2021) 6(12):4342–59. doi: 10.1016/j.bioactmat.2021.04.026

  • CrossRef
  • Google Scholar

• 124

  RossRMaxwellJChandraSLiuXLapineMShawTet al. British Society for Investigative Dermatology Annual. (2019).

  • Google Scholar

• 125

  SyedMH. MRGPRX2 Mediated Mast Cell Responses Are Suppressed by Lactic Acid. Michigan State University (2021).

  • Google Scholar

• 126

  KimDKobayashiTVoisinBJoJ. Single-cell RNA sequencing-guided patient care in refractory drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms. J Invest Dermatol (2019) 139:S170–0. doi: 10.1016/j.jid.2019.03.1056

  • CrossRef
  • Google Scholar

• 127

  JinSRamosR. Computational exploration of cellular communication in skin from emerging single-cell and spatial transcriptomic data. Biochem Soc Trans (2022) 50:297–308. doi: 10.1042/BST20210863

  • CrossRef
  • Google Scholar

• 128

  WolffDet al. National Institutes of Health Consensus Development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2020 highly morbid forms report. Transplant Cell Ther (2021) 27(10):817–35. doi: 10.1016/j.jtct.2021.06.001

  • CrossRef
  • Google Scholar

• 129

  RohK-BJangYChoEParkDKweonDHJungE. Chlorogenic acid isomers isolated from artemisia lavandulaefolia exhibit anti-rosacea effects in vitro. Biomedicines (2022) 10(2):463. doi: 10.3390/biomedicines10020463

  • CrossRef
  • Google Scholar

• 130

  FranklinRA. Fibroblasts and macrophages: Collaborators in tissue homeostasis. Immunol Rev (2021) 302:86–103. doi: 10.1111/imr.12989

  • CrossRef
  • Google Scholar

• 131

  FalangaVIsseroffRRSoulikaAMRomanelliMMargolisDKappSet al. Chronic wounds. Nat Rev Dis Primers (2022) 8(1):50. doi: 10.1038/s41572-022-00377-3

  • CrossRef
  • Google Scholar

• 132

  LeiYTangRXuJWangWZhangBLiuJet al. Applications of single-cell sequencing in cancer research: progress and perspectives. J Hematol Oncol (2021) 14(1):91. doi: 10.1186/s13045-021-01105-2

  • CrossRef
  • Google Scholar

• 133

  SallamMAPrakashSKumbhojkarNShieldsCW4thMitragotriS. Formulation-based approaches for dermal delivery of vaccines and therapeutic nucleic acids: Recent advances and future perspectives. (2021) 6(3): e10215. doi: 10.1002/btm2.10215

  • CrossRef
  • Google Scholar

• 134

  ApaydinDCZakarauskas-SethBICarnevaleLApaydinOPerrottaMCarnevaleRet al. Interferon-γ drives macrophage reprogramming, cerebrovascular remodelling, and cognitive dysfunction in a zebrafish and a mouse model of ion imbalance and pressure overload. Cardiovasc Res (2022) 119(5):1234–49. doi: 10.1093/cvr/cvac188

  • CrossRef
  • Google Scholar

• 135

  JainKK. An overview of drug delivery systems. Methods Mol Biol (2020) 2059:1–54. doi: 10.1007/978-1-4939-9798-5_1

  • CrossRef
  • Google Scholar

• 136

  NourSImaniRChaudhryGRSharifiAM. Skin wound healing assisted by angiogenic targeted tissue engineering: A comprehensive review of bioengineered approaches. J Biomed Mater Res A (2021) 109(4):453–78. doi: 10.1002/jbm.a.37105

  • CrossRef
  • Google Scholar

• 137

  ZhaoMJiangJZhaoMChangCWuHLuQ. The application of single-cell RNA sequencing in studies of autoimmune diseases: a comprehensive review. Clin Rev Allergy Immunol (2021) 60(1):68–86. doi: 10.1007/s12016-020-08813-6

  • CrossRef
  • Google Scholar

• 138

  GaziUGureserASOztekinAKarasartovaDKosar-AcarNDericiMKet al. Skin-homing T-cell responses associated with Demodex infestation and rosacea. Parasite Immunol (2019) 41(8): e12658. doi: 10.1111/pim.12658

  • CrossRef
  • Google Scholar

• 139

  ZhaoZLiuTLiangYCuiWLiDZhangGet al. N2-polarized neutrophils reduce inflammation in rosacea by regulating vascular factors and proliferation of CD4+ T cells. J Invest Dermatol (2022) 142(7):1835–1844. e1832. doi: 10.1016/j.jid.2021.12.009

  • CrossRef
  • Google Scholar

• 140

  DoTPerrieJPellegriniMGudjonssonJMaFModlinRLet al. 373 Identification of immune cell pathways in acne vs. rosacea by single-cell RNA sequencing and single-cell spatial imaging. J Invest Dermatol (2023) 143:S64. doi: 10.1016/j.jid.2023.03.378

  • CrossRef
  • Google Scholar

• 141

  ClarkR. Harnessing Single-Cell Technologies to Understand and Diagnose Rejection in Clinical Face and Upper Extremity Transplantations. Brigham and Women’s Hospital (2020).

  • Google Scholar

• 142

  HardenJLShihYRajendranDHoflandHChangA. LB1144 Quantitative analysis of differentially expressed proteins in papulopustular rosacea. Journal of Investigative Dermatology (2019) 139:B25. doi: 10.1016/j.jid.2019.06.117

  • CrossRef
  • Google Scholar

• 143

  VicinoACochetSPistocchiSConradCRibiCDu PasquierRet al. A severe case of neuroleukemiosis caused by B cell chronic lymphocytic leukemia, presenting as mononeuritis multiplex. J Peripher Nerv Syst (2023) 28(2):266–8. doi: 10.1111/jns.12552

  • CrossRef
  • Google Scholar

• 144

  ZhaoZZhuHLiQLiaoWChenKYangMet al. Skin CD4+ Trm cells distinguish acute cutaneous lupus erythematosus from localized discoid lupus erythematosus/subacute cutaneous lupus erythematosus and other skin diseases. J Autoimmun (2022) 128:102811. doi: 10.1016/j.jaut.2022.102811

  • CrossRef
  • Google Scholar

• 145

  Furlong-SilvaJCrossSDMarriottAEPionnierNArcherJStevenAet al. Tetracyclines improve experimental lymphatic filariasis pathology by disrupting interleukin-4 receptor–mediated lymphangiogenesis. J Clin Invest (2021) 131(5):e140853. doi: 10.1172/JCI140853

  • CrossRef
  • Google Scholar

• 146

  SudarshanKBodaAKDograSBoseIYadavPNAidhenISet al. Discovery of an isocoumarin analogue that modulates neuronal functions via neurotrophin receptor TrkB. Bioorg Med Chem Lett (2019) 29(4):585–90. doi: 10.1016/j.bmcl.2018.12.057

  • CrossRef
  • Google Scholar

• 147

  KeumHYooDJonS. Photomedicine based on heme-derived compounds. Adv Drug Deliv Rev (2022) 182:114134. doi: 10.1016/j.addr.2022.114134

  • CrossRef
  • Google Scholar

• 148

  SonMParkJOhSChoiJShimMKangDet al. Radiofrequency irradiation attenuates angiogenesis and inflammation in UVB-induced rosacea in mouse skin. Exp Dermatol (2020) 29(7):659–66. doi: 10.1111/exd.14115

  • CrossRef
  • Google Scholar

• 149

  NisbetSJTargettDRawlingsAVQianKWangXLinCBet al. Clinical and in vitro evaluation of new anti-redness cosmetic products in subjects with winter xerosis and sensitive skin. Int J Cosmetic Sci (2019) 41:534–47. doi: 10.1111/ics.12559

  • CrossRef
  • Google Scholar

• 150

  LiWWangFGuoRBianZSongY. Targeting macrophages in hematological malignancies: recent advances and future directions. (2022) 15:110. doi: 10.1186/s13045-022-01328-x

  • CrossRef
  • Google Scholar