Session Information
Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud’s – Pathogenesis, Animal Models and Genetics
Session Type: Abstract Submissions (ACR)
Background/Purpose: Systemic sclerosis (SSc) is associated with progressive fibrosis and transforming growth factor β (TGF-β) is implicated in its pathogenesis. Toll-like receptors (TLR) respond to microbial pathogens or injury-associated endogenous danger signals, and aberrant TLR9 signaling is implicated in chronic inflammation, autoimmunity and pulmonary fibrosis. However, the role of TLR9 in fibrogenesis, and the underlying mechanism of action are still unknown.
Methods: TLR9 expression in explanted fibroblasts and mouse skin biopsies was determined. Regulation of fibrotic gene expression and TGF-ß signaling by the TLR9 ligand CpG was examined by real-time PCR, Western blot, transient transfection and immunofluorescence assays. Inhibitors of TLR9 were used to examine the antifibrotic response in vitro.
Results: TLR9 was detected in explanted normal and scleroderma skin fibroblasts, and the skin from mice with bleomycin-induced scleroderma. The TLR9 ligand CpG caused dose-dependent stimulation of collagen and α-smooth muscle actin (ASMA) gene expression along with inflammatory genes. Induction of fibrotic responses was blocked by the TLR9 antagonist iCpG. Moreover, CpG stimulated TGF-β production, TGF-β-mediated responses and canonical Smad signaling, and a neutralizing antibody to TGF-β abolished CpG-induced fibrotic responses. The proteasome inhibitor Bortezomib abrogated CpG-induced stimulation of collagen and ASMA gene expression by disrupting intracellular TLR9 trafficking.
Conclusion: TLR9 activation in fibroblasts is associated with TGF-β-mediated fibrotic responses. Novel small molecule inhibitors of TLR9 already in clinical trial for lupus are sufficient to abrogate these responses, suggesting a potential therapeutic strategy for blocking TLR9 in fibrosis.
Disclosure:
Y. Yang,
None;
F. Fang,
None;
L. Liu,
None;
J. Shangguan,
None;
B. Ye,
None;
J. Varga,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tlr9-signaling-in-fibroblasts-promotes-pro-fibrotic-responses-via-tgf-beta/