High-mobility group box-1 mediates toll-like receptor 4-dependent angiogenesis.
High-mobility group box-1 mediates toll-like receptor 4-dependent angiogenesis.
复制标题
高迁移率 group box-1 介导 Toll 样受体 4 依赖性血管生成。
DOI：
10.1161/atvbaha.111.224048
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发表时间：
2011-05
期刊：
影响因子：
--
通讯作者：
Su SB
中科院分区：
文献类型：
--
作者：
Lin Q;Yang XP;Fang D;Ren X;Zhou H;Fang J;Liu X;Zhou S;Wen F;Yao X;Wang JM;Su SB
炎症与血管生成密切相关，Toll 样受体 (TLR) 是炎症反应的关键介质。然而，TLR 对血管生成的影响尚不完全清楚。在这项研究中，我们确定了 TLR 在血管生成中的参与。在碱诱导角膜新生血管（CNV）的小鼠模型中，我们发现 TLR4−/− 小鼠的 CNV 减弱，但 TLR2−/− 小鼠的 CNV 没有减弱。进一步的研究表明，TLR4 的缺失导致促血管生成因子的产生减少，与伤口部位巨噬细胞积累的减少有关，而这又与高迁移率族蛋白 1 (HMGB1) 蛋白（TLR4 的内源性配体）的表达减少有关。在野生型小鼠中局部应用 HMGB1 到受伤的角膜可促进 CNV，增加巨噬细胞的积累，但在 TLR4−/− 小鼠中则不然。 HMGB1 体外处理还以 TLR4 依赖性方式促进小鼠巨噬细胞产生促血管生成因子。此外，HMGB1 和 TLR4 的拮抗剂减少了野生型小鼠受损角膜中的 CNV 和巨噬细胞的募集。我们的结果表明，伤口中 HMGB1 的释放会引发 TLR4 依赖性反应，从而促进新血管形成。因此，靶向HMGB1-TLR4信号级联可能构成血管生成相关疾病的新治疗方法。
Inflammation is closely linked to angiogenesis, and Toll-like receptors (TLRs) are the key mediators of inflammatory responses. However, the impact of TLRs on angiogenesis is incompletely understood. In this study, we determined the involvement of TLRs in angiogenesis. In a mouse model of alkali-induced corneal neovascularization (CNV), we found that CNV was attenuated in TLR4−/− but not TLR2−/− mice. Further study revealed that the absence of TLR4 led to decreased production of proangiogenic factors in association with reduced accumulation of macrophages at the site of wounds, which was associated with reduced expression of high-mobility group box-1 (HMGB1) protein, an endogenous ligand for TLR4. Topical application of HMGB1 to the injured cornea promoted CNV with increased macrophage accumulation in wild-type mice but not in TLR4−/− mice. HMGB1 treatment in vitro also promoted the production of proangiogenic factors by mouse macrophages in a TLR4-dependent manner. Furthermore, antagonists of HMGB1 and TLR4 reduced CNV and macrophage recruitment in the injured cornea of wild-type mice. Our results suggest that the release of HMGB1 in the wounds initiates TLR4-dependent responses that contribute to neovascularization. Thus, targeting HMGB1-TLR4 signaling cascade may constitute a novel therapeutic approach to angiogenesis-related diseases.