NLRC3-NFAT5途径介导肺募集巨噬细胞代谢损伤在脓毒症宿主继发肺部感染中的作用与机制研究

肺部继发感染是脓毒症后免疫抑制宿主病死的主要原因，但具体机制仍不明。我们前期发现脓毒症后肺部继发感染所募集至肺内的肺募集巨噬细胞（Mo-AM）代谢损伤是其重要原因，进一步机制研究发现相应细胞胞浆内的模式识别受体NLRC3表达增加和候选的可调节代谢与免疫的核转录因子5（NFAT5）表达降低与之有关；而下调小鼠巨噬细胞NLRC3表达可影响NFAT5表达。因此，我们提出研究假说：肺内Mo-AM细胞的NLRC3表达上调通过NFAT5路径介导细胞代谢损伤，促使处于免疫抑制状态的脓毒症宿主继发肺部感染和病死；本项目围绕肺Mo-AM细胞，结合临床患者和NLRC3loxp/loxp小鼠，阐明脓毒症宿主继发肺部感染时肺内Mo-AM细胞的NLRC3-NFAT5轴在细胞代谢损伤中作用与调控机制。本研究将有助于深入认识脓毒症后宿主继发肺部感染和病死的发生机制，并可能为脓毒症的治疗提供新的思路和潜在干预的靶点。

Secondary pulmonary infection is a predominant contributor to the death for septic host after progressing to immunosuppression, but the related mechanism remains to be further identified. Our preliminary study showed that the metabolic impairment of monocyte-derived alveolar macrophages (Mo-AM) recruited by secondary infection is critical for secondary pulmonary infection and death in sepsis. During the course of studying underlying mechanisms, we also found that the upregulated expression of NLRC3, a cytoplasmic pattern recognition receptor, and the decreased expression of nuclear transcription factor 5 (NFAT5), a candidate could modulate the metabolism and immune of cells, are the contributors, while down-regulation of NLRC3 expression in mouse macrophages could upregulate the expression of NFAT5. According these findings we hypothesize that the up-regulated expression of NLRC3 in the Mo-AM of lung can mediate the damage of cell metabolism through the NFAT5 pathway, which may contribute to secondary pulmonary infection and death in the immunosuppressive septic host. Focusing on this working hypothesis, we will uncover the role of Mo-AM and its relative NLRC3 expression in improving the secondary pulmonary infection of immunosuppressive septic host, and their corresponding relationship and regulatory mechanism of NLRC3-NFAT5 axis, and its role in regulating the metabolism of immune response of the Mo-AM. This project might not only provide important mechanistic insights into the pathogenesis of secondary pulmonary infection in sepsis, but also might open new avenue for the future treatment of sepsis.