铜绿假单胞菌是导致院内感染的主要致病菌之一，抗生素耐药现象严重。通过调控宿主免疫抵御铜绿假单胞菌感染是当前治疗学研究的热点。申请人前期发现Egr-1在铜绿假单胞菌感染小鼠的巨噬细胞和肺组织中高表达，并且其表达水平与宿主对铜绿假单胞菌的清除能力呈负相关，但具体机制有待阐释。既往研究发现自体吞噬可调节巨噬细胞的吞噬能力。因此，申请人推测Egr-1通过上调LC3、Atg4等自噬相关蛋白的表达促进自噬体形成，进而降低自噬底物p62的胞内聚集以及抑制NFE2L2介导的清道夫受体MARCO、MSR1的表达，最终导致巨噬细胞的吞噬活性降低从而无法有效清除铜绿假单胞菌。为验证此推测，本项目拟进一步利用免疫学技术、小鼠急性肺炎模型及体外培养骨髓源性巨噬细胞对Egr-1及其通路下游分子在铜绿假单胞菌感染过程中对巨噬细胞吞噬作用的调节机制进行探讨，为实现疾病的靶向免疫治疗累积基础。

Pseudomonas aeruginosa is a multidrug-resistant pathogen that is the second leading cause of nosocomial infections. Nowadays, modulation of host immunity has emerged to be an effective way to defense against P. aeruginosa infection. We recently identified that Egr-1 expression was significantly upregulated in P. aeruginosa-infected mouse macrophages and lung tissues, and Egr-1-deficient mice displayed enhanced bacterial clearance, suggesting that Egr-1 negatively regulates host bactericidal ability during P. aeruginosa infection. Previous studies have shown that autophagy was able to regulate the phagocytic activity of macrophages. Based on the literature and the preliminary data, we hypothesize that Egr-1 promotes autophagosome formation through upregulation of autophagic proteins, including LC3 and Atg4, leading to reduced intracellular aggregation of p62 and decreased NFE2L2-mediated expression of scavenger receptors, MARCO and MSR1, thus resulting in impaired bacterial clearance. In this study, we will apply the mouse model of acute pneumonia and culture bone marrow-derived macrophages for investigating the molecular mechanisms involved in Egr-1-suppressed phagocytic activity using multiple immunological techniques. This study will provide the potential immunotherapeutic target for treatment of P. aeruginosa infection.