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Antimicrobial Peptide LL-37 Drives Rosacea-Like Skin Inflammation in an NLRP3-Dependent Manner

Authors
 Sung-Hyun Yoon  ;  Inhwa Hwang  ;  Eunju Lee  ;  Hyo-Joung Cho  ;  Ju Hee Ryu  ;  Tae-Gyun Kim  ;  Je-Wook Yu 
Citation
 JOURNAL OF INVESTIGATIVE DERMATOLOGY, Vol.141(12) : 2885-2894.e5, 2021-12 
Journal Title
JOURNAL OF INVESTIGATIVE DERMATOLOGY
ISSN
 0022-202X 
Issue Date
2021-12
MeSH
Animals ; Antimicrobial Cationic Peptides / adverse effects* ; Caspase 1 / metabolism ; Cells, Cultured ; Female ; Furans / pharmacology ; Indenes / pharmacology ; Inflammasomes / physiology* ; Inflammation / chemically induced* ; Interleukin-1beta / biosynthesis ; Mice ; Mice, Inbred C57BL ; NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors ; NLR Family, Pyrin Domain-Containing 3 Protein / physiology* ; Rosacea / chemically induced* ; Sulfonamides / pharmacology
Abstract
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 progression 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-1β. 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, intradermal 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+ 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 rosacea pathogenesis.
Full Text
https://www.sciencedirect.com/science/article/pii/S0022202X21010095
DOI
10.1016/j.jid.2021.02.745
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Tae-Gyun(김태균) ORCID logo https://orcid.org/0000-0002-2116-4579
Yu, Je Wook(유제욱) ORCID logo https://orcid.org/0000-0001-5943-4071
Hwang, Inhwa(황인화) ORCID logo https://orcid.org/0000-0001-5235-3519
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/187261
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