title: The Tumor Necrosis Factor Superfamily Molecule LIGHT Promotes Keratinocyte Activity and Skin Fibrosis.
abstract: Several inflammatory diseases including scleroderma and atopic dermatitis display dermal thickening, epidermal hypertrophy, or excessive accumulation of collagen. Factors that might promote these features are of interest for clinical therapy. We previously reported that LIGHT, a TNF superfamily molecule, mediated collagen deposition in the lungs in response to allergen. We therefore tested whether LIGHT might similarly promote collagen accumulation and features of skin fibrosis. Strikingly, injection of recombinant soluble LIGHT into naive mice, either subcutaneously or systemically, promoted collagen deposition in the skin and dermal and epidermal thickening. This replicated the activity of bleomycin, an antibiotic that has been previously used in models of scleroderma in mice. Moreover skin fibrosis induced by bleomycin was dependent on endogenous LIGHT activity. The action of LIGHT in vivo was mediated via both of its receptors, HVEM and LTβR, and was dependent on the innate cytokine TSLP and TGF-β. Furthermore, we found that HVEM and LTβR were expressed on human epidermal keratinocytes and that LIGHT could directly promote TSLP expression in these cells. We reveal an unappreciated activity of LIGHT on keratinocytes and suggest that LIGHT may be an important mediator of skin inflammation and fibrosis in diseases such as scleroderma or atopic dermatitis.
authors: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors: Rana
authors: R
authors: Herro
authors: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors: Ricardo Da S
authors: RDS
authors: Antunes
authors: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors: Amelia R
authors: AR
authors: Aguilera
authors: Department of Immunology, Yamaguchi University School of Medicine, Yamaguchi, Japan.
authors: Koji
authors: K
authors: Tamada
authors: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA. Electronic address: mick@liai.org.
authors: Michael
authors: M
authors: Croft
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007136:Immunoglobulins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007231:Infant, Newborn; D015603:Keratinocytes / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: C498762:CRLF2 protein, human; D007136:Immunoglobulins; D018121:Receptors, Cytokine; D053240:Receptors, Tumor Necrosis Factor, Member 14; C506028:TNFRSF14 protein, human; C505914:TNFSF14 protein, human; C506029:Tnfrsf14 protein, mouse; C505915:Tnfsf14 protein, mouse; C410591:Tslpr protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D001761:Bleomycin; D003094:Collagen