IL-33调控腹腔II型固有淋巴细胞募集在脓毒症发生发展中的作用及其机制

Sepsis is one of the leading causes of death in critically ill patients. The pathogenesis of sepsis is largely unknown, which led to the treatment of sepsis rather limited. Group 2 innate lymphoid cells (ILC2s) play important roles in mucosal immunity, and have been extensively studied in tumor and autoimmune diseases. Our previous study found that a large number of ILC2s were recruited in peritoneal cavity of mice with CLP induced-sepsis, and the expression of CXCR2 was increased significantly after LPS stimulation. As ILC2s highly express IL-33 receptor ST2, and airway epithelial cells-derived IL-33 plays important roles in regulating the recruitment of ILC2s in asthma, we speculate that ILC2s might play critical roles in sepsis, and IL-33 could regulate the recruitment and function of ILC2s in sepsis. Utilizing CLP model mice, ILC2s depletion and ST2 knock-out mice, this project aims to study the critical role of ILC2s in the pathogenesis of sepsis, uncover the molecular mechanisms of IL-33 in regulating the recruitment of ILC2s, and determine the effect of recruited ILC2s regulated IL-33 on the function of celiac macrophage in sepsis. Our study could contribute to understand the pathogenesis of sepsis, and establish early warning system and immune-modulated treatment for sepsis.

脓毒症已成为临床危重病患者最主要的死亡原因之一，发病机制尚未完全明确，因而缺乏特异性治疗方法。II型固有淋巴细胞（ILC2s）是一种具有黏膜免疫功能的免疫细胞，在肿瘤及自身免疫性疾病等领域备受关注。我们的前期研究发现，脓毒症模型小鼠腹腔聚集大量ILC2s，LPS可上调其CXCR2的表达。由于ILC2s高表达IL-33受体ST2，且哮喘气道上皮细胞释放的IL-33对ILC2s募集具有调控作用，因此我们推测，腹腔ILC2s在脓毒症中具有重要作用，IL-33能调控腹腔ILC2s的募集和功能。本项目拟在野生型、ILC2s 缺失型和ST2基因敲除小鼠制备脓毒症模型，在动物、细胞和分子水平上明确ILC2s在脓毒症发生发展中的重要作用；阐述脓毒症中IL-33调控ILC2s募集的分子机制；探讨IL-33介导的ILC2s募集对腹腔巨噬细胞的作用，从而完善脓毒症的发病机制，为脓毒症的预警和免疫调控奠定基础。

脓毒症是临床危重症患者最主要的死亡原因之一，发病机制尚未明确，因此缺乏特异性治疗方法。II型固有淋巴细胞(ILC2s)是一种具有黏膜免疫功能的免疫细胞,在肿瘤及自身免疫性疾病等领域备受关注，而在脓毒症中的具体作用尚不明确。本项目主要通过小鼠脓毒症模型，通过基因敲除小鼠、细胞及分子生物学手段明确ILC2s在脓毒症发生发展中的作用，探讨IL-33调控脓毒症ILC2s募集的分子机制，进一步阐明IL-33介导的ILC2s募集对肺血管内皮细胞及巨噬细胞功能的影响。研究发现脓毒症后ILC2s在腹腔及肺脏中大量募集，部分依赖于IL-33/ST2信号通路。脓毒症时IL-33水平升高，通过调控肺及腹腔中ILC2s的募集，促进细胞因子的分泌。肺脏中募集的ILC2s能够抑制血管内皮细胞焦亡，而腹腔募集的ILC2s能够调控巨噬细胞的死亡和极化。因此，本研究阐明了脓毒症时ILC2s的保护作用，从而调控脓毒症进展，为脓毒症诊治提供了实验基础。