PubMed RSS Feed - -ANTIMICROBIAL PEPTIDE LL-37 DRIVES ROSACEA-LIKE SKIN INFLAMMATION IN AN NLRP3-DEPENDENT MANNER

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J Invest Dermatol. 2021 Mar 18:S0022-202X(21)01009-5. doi: 10.1016/j.jid.2021.02.745. Online ahead of print.

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 interleukin-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. Interestingly, 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, 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.

PMID:33745908 | DOI:10.1016/j.jid.2021.02.745

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