ELMO信号通路介导的中性粒细胞趋化运动在急性肠炎中的作用机制

Neutrophil recruitment to sites of infection is a critical element of the innate immune response that forms the first line of defense against invading pathogens. However, excessive recruitment of these cells results in tissue damage and inflammatory diseases. The process of chemotaxis in neutrophil is guided by concentration gradients of chemokines that released from pathogens or damaged tissues. Many of these chemokines act through G protein-coupled receptors (GPCRs) that regulate actin polymerization and cell migration. However, the pathways linking GPCRs signalling to actin polymerization remain unclear. Recently, we discovered a novel signaling pathway that directly links GPCRs to the actin cytoskeleton through G-protein/ELMO/DOCK complex during chemotaxis in amoeba Dictyostelium discoideum, an ideal eukaryotic model organism for the study of cell chemotaxis. Our preliminary studies in Elmo1 KO mice showed that Elmo1-deficient neutrophils exhibited a severe defect in chemotaxis. In the present study, we set out to investigating the following fundamental questions: 1) What is the role of ELMO1 in neutrophil chemotaxis? 2) What is the mechanism underlying the ELMO1-mediated chemotaxis in neutrophil? 3) Does ELMO1-mediated chemotaxis in neutrophil affect the severity of acute inflammation? The proposed studies are designed to elucidate the function and mechanism of G-protein/ELMO/DOCK signaling pathway in neutrophil chemotaxis and its involvement in inflammation. These studies may lead to new therapeutic strategies for treatment of inflammatory disorders.

中性粒细胞迁移到炎症部位是机体抵御病原体入侵的第一道防线，同时也是导致宿主组织损伤和炎症相关疾病的重要原因。中性粒细胞趋化性所涉及的信号转导机制尚不完全清楚。我们最近在盘基网柄菌中发现了一条全新的调控细胞趋化运动的G蛋白/ELMO/DOCK信号通路。我们进一步的研究发现，Elmo1 KO小鼠的中性粒细胞趋化性显著降低。本课题将在此基础上，利用Elmo1 KO小鼠建立急性肠炎模型，结合共聚焦及双光子显微镜等技术，从分子、细胞、动物整体水平等多个层次开展以下研究：1）明确ELMO1对中性粒细胞趋化性的影响；2）研究ELMO1调控中性粒细胞趋化性的分子机制；3）探讨ELMO1调控中性粒细胞趋化性与炎症反应的关系。本课题将通过深入研究该信号通路对中性粒细胞趋化性的影响和机制及其与炎症反应的关系，为解析通过调控中性粒细胞的趋化性减轻炎症反应提供新的理论依据，为抗炎药物的研究提供新的靶点和研究思路。

中性粒细胞作为固有免疫的主要功能细胞之一，其作用犹如一把双刃剑：在发挥抵御病原微生物入侵作用的同时，也会对周围正常组织造成损伤。临床上，大量的中性粒细胞招募及组织浸润是相关炎症疾病的主要成因。中性粒细胞趋化运动所涉及的信号转导机制尚不完全清楚。中性粒细胞与低等真核生物盘基网柄菌在涉及趋化运动的调控机制方面存在着高度相似性。近年来，我们在盘基网柄菌中发现了一条全新的调控细胞趋化运动的G蛋白/ELMO/DOCK信号通路，但中性粒细胞中是否存在相似的信号通路尚不清楚。本课题利用Elmo1 KO小鼠建立急性肠炎模型，并结合共聚焦激光显微镜技术，从分子、细胞、动物整体水平等多个层次开展了一系列研究，发现来自Elmo1 基因敲除小鼠的中性粒细胞在体内与体外的趋化性都显著降低；ELMO1通过调节Rac1的活性影响细胞骨架肌动蛋白的聚合进而影响中性粒细胞的趋化性，验证了该信号通路在进化上的保守性；应用小鼠急性肠炎模型，我们发现阻断该信号通路导致炎症反应得到一定程度的缓解。这些发现加深了我们对调控中性粒细胞趋化性的分子机制的理解，为炎症相关疾病的抗炎治疗提供一定的理论依据和思路.