Regulation of inflammasome signaling pathway by antimicrobial peptide LL-37

Abstract

Antimicrobial peptides (AMPs) are compounds serving as natural antibiotics. LL-37, the member of cathelicidin antimicrobial peptides, is known to be mainly produced by epithelial cells and crucial role in innate immune response from the first line of host defense after bacterial infection. LL-37 increases or decreases pro-inflammatory cytokines including IFN-β, IL-6 or IL-1β. However, the role of LL-37 in the immune system is not yet clearly understood. Recent studies have proposed that LL-37 is excessively produced in chronic skin diseases such as rosacea and psoriasis. But, the pathogenesis of rosacea has not been studied in detail yet. In this study, I examined the role of LL-37 in the innate immune responses. Here, I demonstrated that LL-37 induces NLRP3 inflammasome activation. I also had found that the mechanism of LL-37-mediated NLRP3 inflammasome activation in bone marrow-derived macrophages (BMDMs). In addition, inhibition of potassium efflux and reduction of intracellular calcium levels failed to trigger the activation of caspase-1 and IL-1β secretion from BMDMs. I had also shown that internalized LL-37 caused lysosomal leakage and cathepsin B-mediated NLRP3 inflammasome activation in BMDMs. Subsequently, I examined the potential effect of the NLRP3 inflammasome complex in rosacea mice model, which induced by LL-37 injection. Interestingly, I observed that the lesion and the release of IL-1β were markedly reduced in Nlrp3-deficient mice, but not in wild type mice. Taken together, I suggest that LL-37-induced NLRP3 inflammasome activation potentially contributes to the pathogenesis of rosacea.