Jiang Dianhua, Liang Jiurong, Li Yuhang, Noble Paul W
Department of Medicine, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Cell Res. 2006 Aug;16(8):693-701. doi: 10.1038/sj.cr.7310085.
The role of Toll-like receptors (TLRs) in pathogen recognition has been expeditiously advanced in recent years. However, investigations into the function of TLRs in non-infectious tissue injury have just begun. Previously, we and others have demonstrated that fragmented hyaluronan (HA) accumulates during tissue injury. CD44 is required to clear HA during tissue injury, and impaired clearance of HA results in unremitting inflammation. Additionally, fragmented HA stimulates the expression of inflammatory genes by inflammatory cells at the injury site. Recently, we identified that HA fragments require both TLR2 and TLR4 to stimulate mouse macrophages to produce inflammatory chemokines and cytokines. In a non-infectious lung injury model, mice deficient in both TLR2 and TLR4 show an impaired transepithelial migration of inflammatory cells, increased tissue injury, elevated lung epithelial cell apoptosis, and decreased survival. Lung epithelial cell overexpression of high molecular mass HA protected mice against acute lung injury and apoptosis, in part through TLR-dependent basal activation of NF-kappaB. The exaggerated injury in TLR2 and TLR4 deficient mice appears to be due to impaired HA-TLR interactions on epithelial cells. These studies identify that host matrix component HA and TLR interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity, and promote recovery from acute lung injury.
近年来，Toll样受体（TLRs）在病原体识别中的作用已得到迅速发展。然而，对TLRs在非感染性组织损伤中的功能研究才刚刚开始。此前，我们和其他人已证明，在组织损伤过程中会积累破碎的透明质酸（HA）。在组织损伤期间清除HA需要CD44，而HA清除受损会导致炎症持续。此外，破碎的HA会刺激损伤部位的炎症细胞表达炎症基因。最近，我们发现HA片段需要TLR2和TLR4共同作用，才能刺激小鼠巨噬细胞产生炎症趋化因子和细胞因子。在非感染性肺损伤模型中，同时缺乏TLR2和TLR4的小鼠炎症细胞的跨上皮迁移受损、组织损伤增加、肺上皮细胞凋亡增加且存活率降低。高分子量HA在肺上皮细胞中的过表达可保护小鼠免受急性肺损伤和凋亡，部分原因是通过TLR依赖的NF-κB基础激活。TLR2和TLR4缺陷小鼠中过度的损伤似乎是由于上皮细胞上HA-TLR相互作用受损。这些研究表明宿主基质成分HA与TLR的相互作用提供了启动炎症反应、维持上皮细胞完整性以及促进急性肺损伤恢复的信号。
