TREM-1诱导的内质网应激在急性肺损伤中的作用研究

Acute lung injury (ALI) is a devastating clinical syndrome with high mortality. Triggering receptor expressed on myeloid cells 1 (TREM-1) is an inflammatory receptor that expresses on the surface of macrophages. Our previous studies have shown that TREM-1 expression is significantly increased in lungs of ALI mice, and inhibition of TREM-1 reduces LPS-induced ALI. However, the exact mechanism remains unclear. We also found that TREM-1 activation up-regulated the endoplasmic reticulum (ER) stress-related proteins, and leaded to ER ultrastructural damage. ER stress is known to be one of the important pathogenic mechanisms of ALI. Therefore, we assume that TREM-1 activation in the lungs can induce ER stress and amplify the inflammatory response, which is one of the mechanisms of ALI. After activation, TREM-1 raises the adapter protein DAP12, activates the intracellular ITAM motif, activates Syk kinase, causes calcium overload and mitochondrial damage, and increases ROS production. ROS is an important factor in initiating ER stress. Therefore, this project will explore whether activation of TREM-1 through the DAP12/Syk pathway to increase ROS production, induce macrophage ER stress, participate in ALI pulmonary inflammation.

急性肺损伤（ALI）是高病死率的急危重症。髓样细胞表达触发受体-1（TREM-1）是表达于巨噬细胞等表面的炎症放大受体，前期研究发现ALI小鼠肺内TREM-1表达显著增加，抑制TREM-1可减轻LPS诱导的小鼠ALI，但机制尚未完全阐明；同时发现激活小鼠巨噬细胞TREM-1可上调内质网（ER）应激相关蛋白，导致ER超微结构破坏。已知ER应激是ALI的重要致病机制之一，因此申请人假设肺内TREM-1激活可诱导ER应激，放大炎症反应，是ALI炎症失控的机制之一。已知TREM-1激活后募集接头蛋白DAP12，并活化胞内ITAM基序，激活Syk激酶，引起钙超载，导致线粒体损伤，增加ROS生成。而ROS是启动ER应激的重要因素。故本项目将探讨激活TREM-1是否通过DAP12/Syk通路增加ROS生成，诱导巨噬细胞ER应激，参与ALI肺内炎症反应失控，进一步明确TREM-1在ALI中致炎的分子机制。

急性肺损伤（ALI）及其严重形式急性呼吸窘迫综合征（ARDS）是当前严重威胁人类生命健康的急危重症，缺乏特异性的治疗措施，病死率高。课题组及他人研究成果强烈提示髓样细胞表达的触发受体1（TREM-1）可能是治疗ALI/ARDS的重要靶点。然而，作为巨噬细胞表面的炎症放大受体，TREM-1参与ALI炎症放大的确切机制尚未完全阐明。本项目提出肺内TREM-1激活通过诱导巨噬细胞内质网（ER）应激，启动和放大肺内炎症失控。因此，本项目从整体动物水平、细胞水平和分子水平系统地阐述了激活巨噬细胞TREM-1受体通过诱导ER应激而促进ALI小鼠肺内炎症失控的作用，并采用ER应激靶向抑制剂、IRE-1α/ XBP-1s通路抑制剂和siRNA技术提示了TREM-1通过激活IRE-1α/ XBP-1s诱导巨噬细胞损伤。此外，本项目拓展性地探讨了：促炎因子IL-18的天然拮抗剂IL-18结合蛋白可通过抑制NF-κB的活化，以及促进Nrf2的抗氧化能力减轻小鼠ALI；临床常用药布地奈德可通过抑制NLRP3炎症小体活化而减轻小鼠ALI。总之，本项目紧密围绕ALI炎症失控，丰富了TREM-1触发炎症的分子机制，为未来可期转化为ALI抗炎新靶点提供了实验基础。