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

• Published in: Immunity (Cambridge, Mass.) Mass.), 2016-07, Vol.45 (1), p.119-130
• 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: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antimicrobial Cationic Peptides; Cathelicidins - genetics; Cathelicidins - metabolism; Cell Differentiation; Cells, Cultured; Dendritic Cells - physiology; Epidermis - pathology; Humans; Interferon-beta - metabolism; Keratinocytes - immunology; Mice; Mice, Knockout; Mitochondria - metabolism; Psoriasis - immunology; RNA, Small Interfering - genetics; Signal Transduction; Wound Healing; Wounds and Injuries - immunology
• 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. [Display omitted] •Keratinocytes co-express IFN-β, LL37, and MAVS in skin wounds and in psoriasis•LL37 enables keratinocytes to produce IFN-β in response to dsRNA from dying cells•LL37 acts through MAVS-dependent activation of TBK1-AKT-IRF3 signaling pathway•IFN-β secreted by activated keratinocytes promotes maturation of dendritic cells The epidermis promotes inflammation in response to injury and in psoriasis. Gallo and colleagues show that this occurs because antimicrobial peptide LL37 enables MAVS and TLR3 in keratinocytes to recognize dsRNA released from necrotic cells. Keratinocytes then produce IFN-β and promote DC activation to facilitate a cutaneous inflammatory response.