Amelioration of Tissue Fibrosis by Toll-like Receptor 4 Knockout in Murine Models of Systemic Sclerosis
Amelioration of Tissue Fibrosis by Toll-like Receptor 4 Knockout in Murine Models of Systemic Sclerosis
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DOI：
10.1002/art.38901
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发表时间：
2015-01-01
影响因子：
13.3
通讯作者：
Sato, Shinichi
中科院分区：
文献类型：
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作者：
Takahashi, Takehiro;Asano, Yoshihide;Sato, Shinichi
客观的。博莱霉素诱导的纤维化和紧皮 (TSK/+) 小鼠是成熟的人类系统性硬化症 (SSc) 实验小鼠模型。越来越多的证据表明 Toll 样受体 (TLR) 在包括 SSc 在内的多种自身免疫性炎症性疾病中发挥着关键作用。本研究旨在确定 TLR-4 在这些小鼠模型纤维化过程中的作用。方法。我们使用 TLR-4(-/-) 小鼠和 TLR-4(-/-) 建立了博来霉素诱导的 SSc 小鼠模型； TSK/+ 小鼠。通过组织学检查、羟脯氨酸测定、酶联免疫吸附测定、实时聚合酶链反应和流式细胞术研究了这两种模型中TLR-4导致病理组织纤维化的机制。结果。与野生型小鼠相比，经博来霉素处理的 TLR-4(-/-) 小鼠的皮肤和肺纤维化减弱。 TLR-4 缺失可抑制博莱霉素治疗诱导的炎症细胞浸润、各种炎症细胞因子的表达和病理性血管生成。此外，在体内对博莱霉素和体外对脂多糖的反应中，成纤维细胞、内皮细胞和免疫细胞中白细胞介素-6 (IL-6) 的表达增加在缺乏 TLR-4 的情况下显着消除。此外，TLR-4 缺失与 B 细胞活化减弱以及对博来霉素治疗的 Th2/Th17 反应偏向相关。重要的是，在 TSK/+ 小鼠（另一种 SSc 小鼠模型）中，废除 TLR-4 可减轻皮下纤维化。结论。这些结果表明 TLR-4 对 SSc 小鼠模型病理组织纤维化的关键贡献。我们的结果表明 TLR-4 信号传导在组织纤维化发展中的关键作用，表明生物分子 TLR-4 靶向可能是 SSc 的潜在治疗方法。
Objective. Bleomycin-induced fibrosis and the tight skin (TSK/+) mouse 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. This study was undertaken to determine the role of TLR-4 in the fibrotic processes in these murine models.Methods. We generated a murine model of bleomycin-induced SSc using TLR-4(-/-) mice and TLR-4(-/-); TSK/+ mice. The mechanisms by which TLR-4 contributes to pathologic tissue fibrosis were investigated in these 2 models by histologic examination, hydroxyproline assay, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and flow cytometry.Results. Dermal and lung fibrosis was attenuated in bleomycin-treated TLR-4(-/-) mice compared with their wild-type counterparts. Inflammatory cell infiltration, expression of various inflammatory cytokines, and pathologic angiogenesis induced by bleomycin treatment were suppressed with TLR-4 deletion. Furthermore, the increased expression of interleukin-6 (IL-6) in fibroblasts, endothelial cells, and immune cells in response to bleomycin in vivo and to lipopolysaccharide in vitro was notably abrogated in the absence of TLR-4. Moreover, TLR-4 deletion was associated with alleviated B cell activation and skew toward a Th2/Th17 response against bleomycin treatment. Importantly, in TSK/+ mice, another SSc murine model, TLR-4 abrogation attenuated hypodermal fibrosis.Conclusion. These results indicate the pivotal contribution of TLR-4 to the pathologic tissue fibrosis of SSc murine models. Our results indicate the critical role of TLR-4 signaling in the development of tissue fibrosis, suggesting that biomolecular TLR-4 targeting might be a potential therapeutic approach to SSc.