dsRNA Released by Tissue Damage Activates TLR3 to Drive Skin Regeneration

•dsRNA released after skin injury triggers skin regeneration via TLR3•IL-6 and Stat3 signaling, downstream mediators of TLR3, are key to regeneration•Loss of TLR3, IL-6Ra, or Stat3 reduces hair neogenesis after wounding•TLR3 induces core hair morphogenetic programs and hair follicle markers

SummaryRegeneration 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.

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