LL-37在S1P2功能缺失脓毒症小鼠肺损伤中的保护作用及机制

Neutrophil is on the first line of innate immune, playing an important role in the pathophysiology of sepsis. The cationic anti-microbial peptide, LL-37, mainly secreted by neutrophil has a function of bacterial clearance and inflammatory response regulation. Studies have showed that S1P2 expressed on the surface of neutrophil and participated in the immune regulation of myeloid cells. Our preliminary study found that S1P2 knock-out (KO) mice was resistant to sepsis-induced ALI, leading to a higher survival rate at 48 h and a lower bacterial load in the lung tissue. In ex vivo experiments, neutrophil isolated from S1P2 KO mice showed upregulated expression of C/EBPε and LL-37. Based on these findings, we speculate that S1P2 may control the expression of LL-37, then influences the bacterial killing and inflammatory response, which contributes to sepsis-induced ALI. This project will elaborate the role and the molecular mechanism of S1P2 in modulating LL-37 expression in the neutrophil, and explore the effect in sepsis-induced ALI on the systemic, cellular and molecular levels. The present study will provide new threads and targets in the prevention and management of ALI.

中性粒细胞在脓毒症致ALI发生、发展中具有关键作用，LL-37作为中性粒细胞的重要阳离子多肽，在其杀菌和炎症反应调控中起明显作用。S1P2表达于中性粒细胞，参与髓系细胞免疫功能的调节。我们前期研究发现：与WT组相比，S1P2 KO脓毒症小鼠48h存活率明显增加，肺损伤程度降低，肺泡灌洗液中细菌负荷明显下降，中性粒细胞LL-37 mRNA及蛋白表达明显上调，C/EBPε mRNA水平增加。因此我们推测：S1P2通过调控脓毒症时中性粒细胞LL-37表达，介导病原微生物的清除和肺部炎症反应，影响脓毒症致ALI的发生和发展。本项目拟从整体、细胞、分子水平，观察小鼠S1P2功能缺失后中性粒细胞LL-37对脓毒症肺组织细菌清除和炎症反应的作用，并探讨S1P2调控LL-37表达的分子机制。本项目将阐明LL-37在S1P2功能缺失脓毒症肺损伤发生发展中的保护作用及机制，为ALI防治提供新思路、新靶向。

中性粒细胞在脓毒症致ALI发生、发展中具有关键作用，LL-37作为中性粒细胞的重要阳离子多肽，在其杀菌和炎症反应调控中起明显作用。S1P2表达于中性粒细胞，参与髓系细胞免疫功能的调节。基于该项目资助，我们主要探讨：1）S1P2通过调控脓毒症时中性粒细胞LL-37表达，介导病原微生物的清除和肺部炎症反应，影响脓毒症致ALI的发生和发展；2）TRPM2抑制巨噬细胞炎性体活化参与ALI的调控机制。我们研究发现：1）与WT组相比，S1P2 KO脓毒症小鼠48h存活率明显增加，肺损伤程度降低，肺泡灌洗液中细菌负荷明显下降，中性粒细胞LL-37 mRNA及蛋白表达明显上调，C/EBPε mRNA水平增加。该工作阐明LL-37在S1P2功能缺失脓毒症肺损伤发生发展中的保护作用及机制。2）巨噬细胞TRPM2缺失可以显著上调巨噬细胞Caspase-1的活化剪切，促进巨噬细胞发生pyroptosis，而抑制ROS通路可以显著降低TRPM2缺失造成的细胞pyroptosis。上述研究工作的开展，可为靶向干预治疗脓毒症致ALI提供理论及实验室基础。

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