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Review
. 2024 Sep 16:15:1367994.
doi: 10.3389/fimmu.2024.1367994. eCollection 2024.

Signaling pathways and targeted therapy for rosacea

Fengjuan Yang #  1   2 , Lian Wang #  1   2 , Deyu Song  1   2 , Lu Zhang  1   2 , Xiaoyun Wang  1   2 , Dan Du  1   2 , Xian Jiang  1   2
Affiliations
Review

Signaling pathways and targeted therapy for rosacea

Fengjuan Yang et al. Front Immunol. .

Abstract

Rosacea is a chronic skin inflammatory disease with a global prevalence ranging from 1% to 20%. It is characterized by facial erythema, telangiectasia, papules, pustules, and ocular manifestations. Its pathogenesis involves a complex interplay of genetic, environmental, immune, microbial, and neurovascular factors. Recent studies have advanced our understanding of its molecular basis, focusing on toll-like receptor (TLR) 2 pathways, LL37 expression, mammalian target of rapamycin (mTOR) activation, interleukin (IL)-17 signaling, transient receptor potential vanilloid (TRPV) functions, and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. LL37-associated signaling pathways, particularly involving TLR2 and mTORC1, are critical in the pathogenesis of rosacea. LL37 interacts with signaling molecules such as extracellular signal-regulated kinases 1 and 2 (ERK1/2), nuclear factor kappa B (NF-κB), inflammasomes, C-X-C motif chemokine ligand 8 (CXCL8), mas-related G-protein-coupled receptor X2 (MRGPRX2)-TRPV4, and vascular endothelial growth factor (VEGF). This interaction activates macrophages, neutrophils, mast cells, and vascular endothelial cells, leading to cytokine release including tumor necrosis factor-alpha (TNF-α), IL-6, IL-1β, C motif chemokine ligand (CCL) 5, CXCL9, and CXCL10. These processes contribute to immune response modulation, inflammation, and angiogenesis in rosacea pathophysiology. The IL-17 signaling pathway also plays a crucial role in rosacea, affecting angiogenesis and the production of inflammatory cytokines. In addition, recent insights into the JAK/STAT pathways have revealed their integral role in inflammatory and angiogenic mechanisms associated with rosacea. Rosacea treatment currently focuses on symptom management, with emerging insights into these molecular pathways providing more targeted and effective therapies. Biological agents targeting specific cytokines, IL-17 inhibitors, JAK inhibitors, and VEGF antagonists are promising for future rosacea therapy, aiming for enhanced efficacy and fewer side effects. This review provides a comprehensive overview of the current knowledge regarding signaling pathways in rosacea and potential targeted therapeutic strategies.

Keywords: pathogenesis; review; rosacea; signaling pathways; targeted therapy.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
Mechanism of LL37 in Rosacea Pathogenesis. LL37 interacts with several key molecules, including Toll-like receptor 2 (TLR2), mechanistic target of rapamycin complex 1 (mTORC1), chemokine (C-X-C motif) ligand 8 (CXCL8), and Mas-related G-protein coupled receptor member X2 (MRGPRX2) linked to transient receptor potential vanilloid 4 (TRPV4). These interactions lead to the activation of various cell types such as macrophages, neutrophils, T cells, mast cells, and plasmacytoid dendritic cells (pDCs). Activation of these cells results in the production of cytokines, playing a critical role in inflammation, immune modulation, and angiogenesis in rosacea. The cytokines produced, such as IL-1β and TNF-α, contribute to the inflammatory responses characteristic of rosacea. The figure showcases the crucial LL37-mediated pathways and their roles in the pathogenesis of rosacea, emphasizing the complex interplay between different cell types and signaling molecules.
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Grants and funding

The author(s) declare financial support was received for the author research, authorship, and/or publication of this article. This research was supported by the National Natural Science Foundation of China (82273559, 82103757), Clinical Research Innovation Project, West China Hospital Sichuan University (19HXCX010), PostDoctor Research Project, West China Hospital, Sichuan University (2020HXBH151).