Inhibition of Toll-like receptor 2 reduces cardiac fibrosis by attenuating macrophage-mediated inflammation
Inhibition of Toll-like receptor 2 reduces cardiac fibrosis by attenuating macrophage-mediated inflammation
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抑制 Toll 样受体 2 通过减轻巨噬细胞介导的炎症来减少心脏纤维化
DOI：
10.1093/cvr/cvt258
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发表时间：
2014-03-01
影响因子：
10.8
通讯作者：
Li, Hui-Hua
中科院分区：
文献类型：
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作者：
Wang, Lei;Li, Yu-Lin;Li, Hui-Hua
Toll 样受体 2 (TLR2) 是先天免疫的重要参与者，最近的研究已确定 TLR2 是心血管疾病的关键介质。在这里，我们研究了TLR2在血管紧张素（Ang）II诱导的心脏纤维化中的参与及其潜在机制。 方法和结果使用用中和抗TLR2抗体（T2.5）处理的TLR2敲除（TLR2 KO）小鼠（B6.129-Tlr2（tm1Kir）/）或野生型（WT）小鼠（C57BL/6）。 Ang II输注（1500 ng/kg/min）后第1、3和7天，心脏中TLR2 mRNA和蛋白的表达显着上调。 TLR2表达增强主要在浸润到心脏的巨噬细胞和中性粒细胞中检测到。敲除 TLR2 和通过中和抗体抑制 TLR2 均可改善 Ang II 诱导的心脏纤维化。这种改善与炎症细胞（尤其是巨噬细胞）浸润的减少、炎症细胞因子、趋化因子的产生以及核因子κB的激活有关。WT和TLR2 KO小鼠之间的骨髓移植实验表明，Ang II诱导的心脏纤维化主要由骨髓来源的炎症细胞介导。从机制上讲，TLR2 的缺陷通过 TGF beta/Smad2/3 途径抑制巨噬细胞依赖性心脏成纤维细胞活化。结论 TLR2 的抑制可通过减弱巨噬细胞募集和心脏炎症反应来预防 Ang II 诱导的心脏纤维化，并可能成为高血压心脏病的新的潜在治疗靶点。
Aims Toll-like receptor 2 (TLR2) is an important player in innate immunity, and recent studies have identified TLR2 as a critical mediator in cardiovascular diseases. Here, we investigated the involvement of TLR2 in angiotensin (Ang) II-induced cardiac fibrosis and the underlying mechanisms.Methods and results TLR2 knockout (TLR2 KO) mice (B6.129-Tlr2(tm1Kir)/) or wild-type (WT) mice (C57BL/ 6) treated with neutralizing anti-TLR2 antibody (T2.5) were used. The expression of TLR2 mRNA and protein in the heart was significantly up-regulated on days 1, 3, and 7 after Ang II infusion (1500 ng/kg/min). Enhanced expression of TLR2 was mainly detected in macrophages and neutrophils that had infiltrated into the heart. Both knockout of TLR2 and inhibition of TLR2 by neutralizing antibody ameliorated cardiac fibrosis induced by Ang II. This improvement was associated with a reduction in the infiltration of inflammatory cells, especially macrophages, the production of inflammatory cytokines, chemokines, and the activation of nuclear factor-kappa B. Bone marrow transplantation experiments between WT and TLR2 KO mice revealed that Ang II-induced cardiac fibrosis is mainly mediated by bone marrow-derived inflammatory cells. Mechanically, the deficiency of TLR2 inhibits macrophage-dependent cardiac fibroblast activation through TGF beta/Smad2/3 pathway.Conclusion Inhibition of TLR2 protects against Ang II-induced cardiac fibrosis by attenuating macrophage recruitment and the inflammatory response in the heart and may be a novel potential therapeutic target for hypertensive heart disease.