title: Antimicrobial Peptide LL37 and MAVS Signaling Drive Interferon-β Production by Epidermal Keratinocytes during Skin Injury.
abstract: 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.
authors.affiliation: Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ling-Juan
authors.initials: LJ
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, San Diego, La Jolla, CA 92093, USA.
authors.forename: George L
authors.initials: GL
authors.lastname: Sen
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Ward
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Johnston
authors.affiliation: Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Chun
authors.affiliation: Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, San Diego, La Jolla, CA 92093, USA.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Adase
authors.affiliation: Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Sanford
authors.affiliation: Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Gao
authors.affiliation: Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Chensee
authors.affiliation: Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Emi
authors.initials: E
authors.lastname: Sato
authors.affiliation: Department of Dermatology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fritz
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jaymie
authors.initials: J
authors.lastname: Baliwag
authors.affiliation: Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Williams
authors.affiliation: Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Tissa
authors.initials: T
authors.lastname: Hata
authors.affiliation: Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: rgallo@ucsd.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000502:physiology*; D004817:Epidermis / Q000473:pathology*; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism; D015603:Keratinocytes / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D011565:Psoriasis / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014945:Wound Healing; D014947:Wounds and Injuries / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D016899:Interferon-beta; D034741:RNA, Small Interfering; C512612:MAVS protein, mouse