Antimicrobial Peptide LL37 and MAVS Signaling Drive Interferon-[beta] Production by Epidermal Keratinocytes during Skin Injury

• Published in: Immunity (Cambridge, Mass.) Vol. 45; no. 1; p. 119
• Main Authors: Zhang, Ling-juan, Sen, George L, Ward, Nicole L, Johnston, Andrew, Chun, Kimberly, Chen, Yifang, Adase, Christopher, Sanford, James A, Gao, Nina, Chensee, Melanie, Sato, Emi, Fritz, Yi, Baliwag, Jaymie, Williams, Michael R, Hata, Tissa, Gallo, Richard L
• Format: Journal Article
• Language: English
• Published: Cambridge Elsevier Limited 19.07.2016
• Subjects: Interferon; Neutrophils; Psoriasis; Skin diseases; Tumor necrosis factor-TNF
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2016.06.021

Type 1 interferons (IFNs) promote inflammation in the skin but the mechanisms responsible for inducing these cytokines are not well understood. We found that IFN-β was abundantly produced by epidermal keratinocytes (KCs) in psoriasis and during wound repair. KC IFN-β production depended on stimulation of mitochondrial antiviral-signaling protein (MAVS) by the antimicrobial peptide LL37 and double stranded-RNA released from necrotic cells. MAVS activated downstream TBK1 (TANK-Binding Kinase 1)-AKT (AKT serine/threonine kinase 1)-IRF3 (interferon regulatory factor 3) signaling cascade leading to IFN-β production and then promoted maturation of dendritic cells. In mice, the production of epidermal IFN-β by LL37 required MAVS, and human wounded and/or psoriatic skin showed activation of MAVS-associated IRF3 and induction of MAVS and IFN-β gene signatures. These findings show that KCs are an important source of IFN-β and MAVS is critical to this function, and demonstrates how the epidermis triggers unwanted skin inflammation under disease conditions.