Session Information
Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud’s – Pathogenesis, Animal Models and Genetics
Session Type: Abstract Submissions (ACR)
Background/Purpose:
Recent studies implicate innate immune signaling and Toll like receptor-4 (TLR4) in fibrogenesis. We hypothesized that injury in scleroderma leads to tissue accumulation of damage-associated molecules such as fibronectin-EDA (Fn-EDA), which serve as endogenous ligands for TLR4. We sought to characterize the expression, mechanism of action and potential fibrogenic role of Fn-EDA. We further investigated the effect of pharmacological inhibition of TLR4 signaling on fibrogenesis.
Methods:
TLR4 expression and Fn-EDA production and accumulation were evaluated in scleroderma skin biopsies and sera, in explanted normal and scleroderma skin fibroblasts, and in mouse models of scleroderma. The fibrogenic effect of Fn-EDA-TLR4 signaling was evaluated in explanted normal and scleroderma skin fibroblasts and in human organotypic skin raft cultures. The role of Fn-EDA in fibrogenesis was further evaluated using Fn-EDA-null mice. The effect of pharmacological inhibition of TLR4 signaling was evaluated in experimental models of dermal fibrosis and in explanted scleroderma fibroblasts.
Results:
Fn-EDA was markedly elevated in scleroderma serum and skin biopsies, and in lesional tissues from mice with bleomycin-induced scleroderma. Microarray analysis showed elevated Fn-EDA mRNA levels in skin biopsies from patients with diffuse cutaneous scleroderma. Explanted scleroderma fibroblasts in organotypic skin raft cultures produced elevated Fn-EDA and deposited it into the matrix. Fn-EDA stimulated collagen synthesis and myofibroblasts differentiation in vitro, and induced dermal sclerosis in the skin equivalent. The profibrotic effects of Fn-EDA were TLR4-dependent and mediated via the microRNA miR29. Pharmacological TLR4 disruption using a novel small molecule inhibitor, or genetic deletion of Fn-EDA, protected mice from the development of skin fibrosis.
Conclusion:
Together, these complementary in vitro and in vivo experiments firmly implicate TLR4-mediated innate immune signaling and aberrant Fn-EDA production and accumulation in driving persistent fibroblast activation and progressive fibrogenesis. Disrupting the TLR4-Fn-EDA axis by either preventing Fn-EDA accumulation, or blocking TLR4 signaling using selective small molecule inhibitors, represent appealing novel strategies for treating scleroderma.
Disclosure:
S. Bhattacharyya,
None;
Z. Tamaki,
None;
W. Wang,
None;
P. Hoover,
None;
A. Booth,
None;
A. Dreffs,
None;
M. E. Hinchcliff,
None;
F. Fang,
None;
S. Getsios,
None;
H. Yin,
None;
E. S. White,
None;
J. Varga,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/damage-associated-endogenous-tlr4-ligand-fibronectin-eda-is-overexpressed-in-scleroderma-and-drives-persistent-fibrosis-via-tlr4-and-inhibition-of-tlr4-prevents-and-reverses-experimental-dermal-fibros/