Session Type: Abstract Submissions (ACR)
Background/Purpose: Bleomycin (BLM)-induced fibrosis model and tight skin mice (TSK/+) model are well-established experimental murine models of human systemic sclerosis (SSc). Growing evidence has demonstrated the pivotal role of Toll-like receptors (TLRs) in several autoimmune inflammatory diseases including SSc. The aim of this study is to determine the role of TLR4 in the fibrotic process in these models.
Methods: We generated a BLM-induced SSc murine model with mice deficient for TLR4. The mechanism by which TLR4 contributes to this fibrotic model was investigated with histologic examination, hydroxyproline assay, ELISA, real-time PCR, and flow cytometry. In addition, to examine the role of TLR4 in less inflammatory fibrotic model, we also investigated fibrosis in TSK/+ mice lacking TLR4.
Results: Dermal and lung fibrosis was attenuated in BLM-treated TLR4-/- mice compared with their wild type counterparts. Consistently, inflammatory cell infiltration, expression of various inflammatory cytokines, pathological angiogenesis, hypergammaglobulinemia and elevated titer of anti-DNA topoisomerase I antibody induced by BLM treatment were suppressed with TLR4 deletion. Furthermore, the increased expression of interleukin (IL)-6 in fibroblasts, endothelial cells, and immune cells in response to BLM in vivo and to LPS in vitrowas remarkably abrogated in the absence of TLR4. Moreover, TLR4 deletion was associated with alleviated skew in Th2/Th17 response against BLM treatment. In parallel with these observations, TLR4 abrogation attenuated skin fibrosis in TSK/+ mice as well.
Conclusion: These results indicate the pivotal contribution of TLR4 to the pathogenesis in a BLM-induced SSc murine model and TSK/+ model, two major models which mimic early and late phase of SSc respectively. Our results indicate the critical role of TLR4 signaling in the pathogenesis of fibrosis, suggesting that the biomolecular TLR4 targeting might be a potential therapeutic approach to SSc.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/potential-roles-of-toll-like-receptor-4-in-the-murine-models-of-systemic-sclerosis/