title: dsRNA Released by Tissue Damage Activates TLR3 to Drive Skin Regeneration.
abstract: Regeneration of skin and hair follicles after wounding--a process known as wound-induced hair neogenesis (WIHN)--is a rare example of adult organogenesis in mammals. As such, WIHN provides a unique model system for deciphering mechanisms underlying mammalian regeneration. Here, we show that dsRNA, which is released from damaged skin, activates Toll-Like Receptor 3 (TLR3) and its downstream effectors IL-6 and STAT3 to promote hair follicle regeneration. Conversely, TLR3-deficient animals fail to initiate WIHN. TLR3 activation promotes expression of hair follicle stem cell markers and induces elements of the core hair morphogenetic program, including ectodysplasin A receptor (EDAR) and the Wnt and Shh pathways. Our results therefore show that dsRNA and TLR3 link the earliest events of mammalian skin wounding to regeneration and suggest potential therapeutic approaches for promoting hair neogenesis.
authors.affiliation: Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Nelson
authors.affiliation: Department of Plastic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Sashank K
authors.initials: SK
authors.lastname: Reddy
authors.affiliation: Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Tabetha S
authors.initials: TS
authors.lastname: Ratliff
authors.affiliation: Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: M Zulfiquer
authors.initials: MZ
authors.lastname: Hossain
authors.affiliation: Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Adiya S
authors.initials: AS
authors.lastname: Katseff
authors.affiliation: Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Amadeus S
authors.initials: AS
authors.lastname: Zhu
authors.affiliation: Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Chang
authors.affiliation: Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Sydney R
authors.initials: SR
authors.lastname: Resnik
authors.affiliation: Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Carly
authors.initials: C
authors.lastname: Page
authors.affiliation: Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Dongwon
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Whittam
authors.affiliation: Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Lloyd S
authors.initials: LS
authors.lastname: Miller
authors.affiliation: Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Electronic address: lag@jhmi.edu.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Garza
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D005260:Female; D005838:Genotype; D018859:Hair Follicle / Q000254:growth & development; D006801:Humans; D007231:Infant, Newborn; D015850:Interleukin-6 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D012330:RNA, Double-Stranded / Q000378:metabolism*; D012038:Regeneration; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D014945:Wound Healing; D000075746:Zinc Finger Protein Gli2; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015415:Biomarkers; C000618551:Gli2 protein, mouse; D015850:Interleukin-6; D051741:Kruppel-Like Transcription Factors; D012330:RNA, Double-Stranded; D050796:STAT3 Transcription Factor; D051196:Toll-Like Receptor 3; D000075746:Zinc Finger Protein Gli2; D051176:beta Catenin