- •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
dsRNA Released by Tissue Damage Activates TLR3 to Promote Regeneration
IL-6 and pSTAT3 Are Induced by Tissue Damage and dsRNA
TLR3 Effects on Regeneration Are Mediated by IL-6 and pSTAT3
- Blaskovich M.A.
- Sun J.
- Cantor A.
- Turkson J.
- Jove R.
- Sebti S.M.
TLR3 Activation Alters Keratinocyte Differentiation and Induces Markers of Hair Follicle Progenitors
- Garza L.A.
- Yang C.C.
- Zhao T.
- Blatt H.B.
- Lee M.
- He H.
- Stanton D.C.
- Carrasco L.
- Spiegel J.H.
- Tobias J.W.
- Cotsarelis G.
Hair Follicle Morphogenetic Pathways Are Induced by TLR3 Signaling
dsRNA Are Damage-Associated Signals that Promote Regeneration
TLR3 Activation Increases Markers of Hair Follicle Progenitors
TLR3 Activation Initiates Hair Morphogenesis
|Experiment||Mouse Strain||Number of Mice||Intervention||Day of Intervention||Day of CSLM Assessment|
|High versus low gene expression–early; high versus low gene expression–late||C57 versus C57 × FVB × SJL C57 × FVB × SJL||4 per strain; 3 per group||none||–||wound closure; ∼WD20-24|
|Standard WIHN versus fringe Cuts||C57BL/6J||14–15 per group||10 cuts per side||WD0||∼WD20-24|
|Exogeneous poly (I:C) addition||C57 × FVB × SJL; B6;129S1-Tlr3tm1Flv/J||10–11 per group; 9 per group||500 ng Poly IC injected into wound||WD3||∼WD20-24|
|Rnase III addition||C57 × FVB × SJL||17–19 per group||15 units Rnase III injected into wound||WD3||∼WD20-24|
|WIHN in TLR3 KO||B6;129S1-Tlr3tm1Flv/J; B6;129SF2/J||6 per group||none||–||∼WD20-24|
|Exogeneous IL-6 addition||C57BL/6J; B6N.129S1-Tlr3tm1Flv/J||30 per group; 8–10 per group||25 ng rmIL-6 protein injected into wound; 500 ng rmIL-6 protein injected into wound||WD7||∼WD20-24|
|Importance of IL-6Rα||K14-ERT2-Cre × IL-6Ralpha fl/fl (both C57BL/6)||3–6 per group||intraperitoneal tamoxifin every other day||WD5-WD14||∼WD20-24|
|Cucurbitacin I||C57 × FVB × SJL||10–14 per group||2 mg/kg cucurbitacin I injected into wound||WD7||∼WD20-24|
|Importance of Stat3 in WIHN||K5-ERT2-Cre × Stat3 fl/fl (both C57BL/6)||10–15 per group||I.P. tamoxifin every other day||WD0-WD14||∼WD20-24|
|Role of T and B cells||NOD.Cg-PrkdcscidIl2rgtm1Wjl (NOD/ShiLt)||5||none||–||∼WD20-24|
Gene Expression Analysis
Immunohistochemistry, Immunocytochemistry, and Histology
- Document S1. Supplemental Experimental Procedures and Figures S1–S5
- Establishment of dorsal-ventral polarity in the Drosophila embryo: the induction of polarity by the Toll gene product.Cell. 1985; 42: 791-798
- The canonical Wnt/beta-catenin signalling pathway.Methods Mol. Biol. 2008; 468: 5-15
- Leucine-rich repeat-containing G-protein-coupled receptors as markers of adult stem cells.Gastroenterology. 2010; 138: 1681-1696
- Ultraviolet radiation damages self noncoding RNA and is detected by TLR3.Nat. Med. 2012; 18: 1286-1290
- Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice.Cancer Res. 2003; 63: 1270-1279
- Regeneration of hair follicles and sebaceous glands from the epithelium of scars in the rabbit.Cancer Res. 1954; 14: 575-579
- Regeneration as an evolutionary variable.J. Anat. 2001; 199: 3-11
- CellProfiler: image analysis software for identifying and quantifying cell phenotypes.Genome Biol. 2006; 7: R100
- Age-associated inflammation inhibits epidermal stem cell function.Genes Dev. 2012; 26: 2144-2153
- Characterization and quantification of wound-induced hair follicle neogenesis using in vivo confocal scanning laser microscopy.Skin Res. Technol. 2011; 17: 387-397
- The regenerative activity of interleukin-6.Methods Mol. Biol. 2013; 982: 59-77
- Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells.J. Clin. Invest. 2011; 121: 613-622
- Fgf9 from dermal γδ T cells induces hair follicle neogenesis after wounding.Nat. Med. 2013; 19: 916-923
- Principles of interleukin (IL)-6-type cytokine signalling and its regulation.Biochem. J. 2003; 374: 1-20
- Selective activation of thrombin is a critical determinant for vertebrate lens regeneration.Curr. Biol. 2003; 13: 877-881
- Summaries of Affymetrix GeneChip probe level data.Nucleic Acids Res. 2003; 31: e15
- Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding.Nature. 2007; 447: 316-320
- Advances in the regulation of liver regeneration.Expert Rev. Gastroenterol. Hepatol. 2011; 5: 105-121
- mRNA is an endogenous ligand for Toll-like receptor 3.J. Biol. Chem. 2004; 279: 12542-12550
- Human papillomavirus deregulates the response of a cellular network comprising of chemotactic and proinflammatory genes.PLoS ONE. 2011; 6: e17848
- The formation of vellus hair follicles from human adult epidermis.J. Invest. Dermatol. 1956; 27: 19-23
- Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury.Nat. Med. 2009; 15: 1377-1382
- Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9.J. Invest. Dermatol. 2007; 127: 331-341
- Activation of innate immunity is required for efficient nuclear reprogramming.Cell. 2012; 151: 547-558
- Toll-like receptor 3 ligand polyinosinic:polycytidylic acid promotes wound healing in human and murine skin.J. Invest. Dermatol. 2012; 132: 2085-2092
- Keratin 15 promoter targets putative epithelial stem cells in the hair follicle bulge.J Invest. Dermatol. 2003; 121: 963-968
- Key differences in TLR3/poly I:C signaling and cytokine induction by human primary cells: a phenomenon absent from murine cell systems.Blood. 2007; 110: 3245-3252
- TLR3 activation evokes IL-6 secretion, autocrine regulation of Stat3 signaling and TLR2 expression in human bronchial epithelial cells.J. Cell Commun. Signal. 2013; 7: 109-118
- Molecular mechanisms regulating hair follicle development.J. Invest. Dermatol. 2002; 118: 216-225
- Epithelial Wnt ligand secretion is required for adult hair follicle growth and regeneration.J. Invest. Dermatol. 2013; 133: 31-41
- Prostaglandin D2 inhibits wound-induced hair follicle neogenesis through the receptor, Gpr44.J. Invest. Dermatol. 2013; 133: 881-889
- Planarian regeneration: its end is its beginning.Cell. 2006; 124: 241-245
- Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin.Science. 2010; 327: 1385-1389
- Sonic hedgehog signaling is essential for hair development.Curr. Biol. 1998; 8: 1058-1068
- Epithelial stem cells in adult skin.Curr. Top. Dev. Biol. 2014; 107: 109-131
- Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice.J. Immunol. 1998; 161: 4652-4660
- Sonic hedgehog (shh) expression in developing and regenerating axolotl limbs.J. Exp. Zool. 1999; 284: 197-206
- Toll-like receptors and Type I interferons.J. Biol. Chem. 2007; 282: 15319-15323
- Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-alpha through bone morphogenic protein-2.Am. J. Pathol. 2010; 176: 2247-2258
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