巨噬细胞分泌包含GBP2的外泌体激活NLRP3炎症小体诱导II 型肺泡上皮细胞焦亡：急性肺损伤的新机制

外泌体介导的细胞间对话是目前的研究热点。脂多糖（LPS）是促急性肺损伤(ALI)的重要物质，通过活化巨噬细胞（MΦ），引起II型肺泡上皮细胞（AT-II）损伤及炎性反应，促进ALI的发生。但是，外泌体如何介导上述两种细胞间的对话鲜见报道。我们的前期研究发现：LPS可诱导MΦ分泌的外泌体中GBP2含量增加；LPS诱导的MΦ外泌体可激活AT-II 及小鼠肺脏NLRP3炎症小体，并诱发小鼠ALI，然而机制不明。因此，我们设想：LPS诱导MΦ释放包含GBP2的外泌体，直接激活AT-II细胞NLRP3炎症小体，引起焦亡从而促进ALI。本研究拟从体内外层面探讨TMBIM1调控巨噬细胞分泌GBP2外泌体的机理；从蛋白结构层面分析GBP2通过正负电荷吸引与AT-II 内NLRP3炎症小体相互作用并诱导细胞焦亡；血管紧张素 (1-7) 如何抑制上述效应。本课题为ALI的防治提供新策略。

Cell communication via exosomes has been a research highlight recently. Lipopolysaccharide (LPS) is proved to be one of the noxious substances causing cell injury and inflammatory in alveolar type II cells (AT-II) through activating macrophages, in a result, aggravating acute lung injury (ALT). However, how exosomes mediate the communication between macrophages and AT-II is largely unknown. Our previous study has confirmed that LPS was capable of increasing the expression of GBP2 in exosomes derived from macrophages, as well as activating NLRP3 inflammasomes in AT-II and lung tissues of mouse, which gave rise to the ALT. Nevertheless, the underlying mechanism remains unclear. Consequently, to explore the underlying mechanism, we hypothesize that exosomes containing GBP2 released from LPS-pretreated macrophages could directly activate NLRP3 inflammasomes via the positive and negative interactions to initiate AT-II pyroptosis, leading to the exacerbation of ALT in mouse. In this context, we will perform in vivo and in vitro experiments to explore the mechanism in which TMBIM1 regulates the GBP2-abandunt-exosomes secretion from the macrophages, as well as the pyroptosis resulted from the interaction between GBP2 and NLRP3 inflammasomes at protein level. Additionally, Angiotensin (1-7), which has been demonstrated to decrease NLRP3 inflammasomes, will be introduced to test if it could inhibit the above-mentioned pathological process of ALT induced by LPS. This project provides a novel strategy for acute lung injury prevention and therapy.