Session Information
Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics I
Session Type: Abstract Submissions (ACR)
Background/Purpose
Our recent studies implicate innate immune signaling through Toll like receptor 4 (TLR4) in scleroderma pathogenesis. Aberrant production and accumulation of the endogenous TLR4 ligand Fn-EDA drives TLR4-dependent persistent fibroblast activation and progressive fibrogenesis in scleroderma. The goal of these studies is to evaluate the antifibrotic potential of pharmacological TLR4 blockade in organ fibrosis.
Methods
For this study, we used TLR4 intracellular signaling inhibitor TAK242. The effect of TAK242 was investigated in normal dermal fibroblasts activated with TLR4 ligands or scleroderma fibroblasts by Western blot analysis, immunofluorescence and real-time qPCR; and in 3-D organotypic human skin equivalents reconstituted with scleroderma fibroblasts. The effect of TLR4 inhibition by TAK242 was examined in vivo by local subcutaneous injection of bleomycin (BLM) to induce dermal and pulmonary fibrosis in 6- to 8-week-old female mice (C57BL/6J).
Results
TAK242 treatment ameliorated dermal and pulmonary fibrosis and reduced the expression of pro-inflammatory and pro-fibrotic mediators in the skin of BLM-treated mice compared to vehicle-treated wildtype control mice. Importantly, TAK242 induced the regression of pre-established organ fibrosis. In vitro, TAK242 abrogated TLR4-induced stimulation of collagen synthesis and myofibroblasts differentiation in explanted normal skin fibroblasts, and in constitutively active scleroderma fibroblast populating 3D skin equivalents. The antifibrotic effects of TAK242 were accompanied by reduced activation of TLR4 signaling.
Conclusion
Our results provide evidence that specific TLR4 inhibitor TAK242 attenuates organ fibrogenesis both in vitro and in vivo. These findings identify TAK242 as a potential novel strategy for breaking the cycle of progressive fibrosis in scleroderma and other fibrotic diseases.
Disclosure:
S. Bhattacharyya,
None;
W. Wang,
None;
Z. Tamaki,
None;
Y. Tsukimi,
None;
M. Yamasaki,
None;
J. Varga,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/blockade-of-tlr4-signaling-by-tak242-ameliorates-experimental-organ-fibrosis/