期刊
JOURNAL OF INVESTIGATIVE DERMATOLOGY
卷 141, 期 12, 页码 2885-+出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2021.02.745
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资金
- National Research Foundation of Korea - Korean Government [2015M3A9B6073856, 2020R1A2B5B02001823, 2020R1A4A1019009]
- National Research Foundation of Korea [2020R1A2B5B02001823, 2015M3A9B6073856] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Rosacea is a chronic inflammatory skin disease characterized by erythema and pustules, and its pathogenesis may be associated with increased levels of antimicrobial peptide LL-37. Research has shown that NLRP3 inflammasome activation plays a crucial role in LL-37-induced skin inflammation and rosacea pathogenesis.
Rosacea is a chronic inflammatory skin disease characterized by immune response-dependent erythema and pustules. Although the precise etiology of rosacea remains elusive, its pathogenesis is reportedly associated with an increased level of antimicrobial peptide LL-37. However, molecular mechanisms underlying the pro-gression of rosacea via LL-37 remain poorly understood. Here, we examined the potential role of LL-37 in rosacea-like skin inflammatory phenotypes at a molecular level. Our in vitro data demonstrated that LL-37 promotes NLRP3-mediated inflammasome activation in lipopolysaccharide-primed macrophages, indicated by the processing of caspase-1 and IL-10. LL-37 was internalized into the cytoplasm of macrophages through P2X7 receptor-mediated endocytosis. Intracellular LL-37 triggered the assembly and activation of NLRP3-ASC inflammasome complex by facilitating lysosomal destabilization. Consistent with these in vitro results, intra-dermal LL-37 administration induced in vivo caspase-1 activation and ASC speck formation in the skin of Nlrp3- expressing, but not in Nlrp3-deficient, mice. Intradermal injection of LL-37 elicited profound recruitment of inflammatory Gr1 thorn cells and subsequent skin inflammation. However, LL-37-induced rosacea-like skin inflammation was significantly abrogated in Nlrp3-deficient mice. Furthermore, an NLRP3-specific inhibitor, MCC950, markedly reduced LL-37-triggered rosacea-like phenotypes. Taken together, our findings clearly indicate that NLRP3 inflammasome activation plays a crucial role in LL-37-induced skin inflammation and ro-sacea pathogenesis.
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