An antimicrobial peptide cathelicidin is increased in inflamed skin. An active form of cathelicidin, LL37 has immunomodulatory effects in addition to antimicrobial activity. LL37 is implicated in the pathogenesis of various skin diseases such as psoriasis, rosacea, dermatomyositis, scleroderma, and lupus erythematosus. We previously showed that LL37 binds to self dsRNA, and that complex of LL37 and self dsRNA uptake into cytoplasm is dependent on scavenger receptor (SR)-mediated endocytosis, followed by recognition of dsRNA by toll-like receptor (TLR) 3 and cytosolic RNA sensors, and by induction of inflammatory cytokines. Additionally, LL37 provokes inflammation and angiogenesis by itself. However, the specific mechanism how LL37 exhibits those functions is not well understood. The aim of this study is to clarify how LL-37 acts on the cell surface and within the cell. We first classified the genes induced by LL37 and/or mock viral dsRNA poly(I:C) in keratinocytes using DNA microarray. The combination of LL37 and poly(I:C) elicited inflammatory genes including tumor necrosis factor (TNF)-α, CXCL10, and interferon (IFN)-β. The expression of those genes was suppressed by the inhibition of SRs, endocytosis, TLR3, and mitochondrial antiviral-signaling protein (MAVS). On the other hand, sole LL37 increased the expression of genes related to angiogenesis, cyclooxygenase (COX)-2, vascular endothelial growth factor (VEGF)-A, and so on. Interestingly, this induction was abrogated by repression of SRs as well as endocytosis inhibitors. Besides, the proximity ligation assay (PLA) revealed that sole LL37 as well as conjugate of LL37 and poly(I:C) contacts with SRs on the cell surface. These results indicate that complex of LL37 and poly(I:C) promotes immunological functions by entering cells through endocytosis mediated by membrane receptors such as SR. Moreover, sole LL37 is taken up into cytoplasm via SRs and following endocytosis mainly, similar to combination of LL37 and poly(I:C), suggesting that inhibition of SR may be a new potential therapeutic target.

ESDR326 - An antimicrobial peptide LL37 facilitates immunological functions via multiple cell surface receptors

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.