title: A synthetic TLR3 ligand mitigates profibrotic fibroblast responses by inducing autocrine IFN signaling.
abstract: Activation of TLR3 by exogenous microbial ligands or endogenous injury-associated ligands leads to production of type I IFN. Scleroderma patients with progressive skin fibrosis display an IFN-regulated gene signature, implicating TLR3 signaling in the disease. In this study, we show that TLR3 expression was detected on foreskin, adult skin, and lung fibroblasts, and TLR3 levels were significantly elevated in a subset of scleroderma skin biopsies. In explanted skin and lung fibroblasts, the synthetic TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)), a dsRNA analog, caused dose- and time-dependent stimulation of IFN-β production and generation of an IFN-response gene signature that was accompanied by substantial downregulation of collagen and α-smooth muscle actin gene expression. Furthermore, poly(I:C) abrogated TGF-β-induced fibrotic responses and blocked canonical Smad signaling via upregulation of inhibitory Smad7. Surprisingly, the inhibitory effects of poly(I:C) in fibroblasts were independent of TLR3 and were mediated by the cytosolic receptors retinoic acid-inducible gene 1 and melanoma differentiation-associated gene 5, and involved signaling via the IFN receptor. Taken together, these results demonstrate that induction of a fibroblast IFN response gene signature triggered by dsRNA is associated with potent TLR3-independent anti-fibrotic effects. The characteristic IFN response gene signature seen in scleroderma lesions might therefore signify a tissue-autonomous protective attempt to restrict fibroblast activation during injury.
authors: Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Feng
authors: F
authors: Fang
authors: Kohtaro
authors: K
authors: Ooka
authors: Xiaoyong
authors: X
authors: Sun
authors: Ruchi
authors: R
authors: Shah
authors: Swati
authors: S
authors: Bhattacharyya
authors: Jun
authors: J
authors: Wei
authors: John
authors: J
authors: Varga
mesh_terms: D000328:Adult; D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007372:Interferons / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D018613:Microscopy, Confocal; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D059467:Transcriptome; D014162:Transfection
chemical_list: D008024:Ligands; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D007372:Interferons
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