NAMPT调控CD4+T细胞焦亡在脓毒症免疫抑制中的作用

Sepsis is a common syndrome in patients with severe trauma, infection and major operations. It addresses a formidable challenge for clinicians. Immunosuppression and the following secondary infection, are leading causes of sepsis-related mortality. Excessive programmed cell death(PCD) of immune cells, including B lymphocytes, CD4+T lymphocytes, macrophages and dendritic cells, is a critical mechanism of sepsis induced immunosuppression. Previous reports indicated that apoptosis was the major form of PCD of immune cells. Accumulating evidences have shown that pyroptosis, another form of PCD, is closely associated with the onset of endotoxic shock. Our previous research found that pyroptosis contributed to immune cell death in murine cecum ligation and puncture (CLP) model of severe sepsis.  Nicotinamide phosphoribosyl transferase （NAMPT） inhibitor FK866 could decrease the percentage of CD4+/caspase-1+ cells, and down-regulate plasma level of IL-1β and IL-18. These results indicated that FK866 could alleviate CD4+ T cell pyroptosis in sepsis. In the present proposal, we will conduct the following study: 1. To determine the relation between NAMPT and CD4+T cell pyroptosis and its clinical significance ; 2. To explore the role of NAMPT in CD4+T cell pyroptosis in CLP septic mice; 3. To elucidate the underlying molecular mechanisms of NAMPT in CD4+T cell pyroptosis in sepsis. The successful fulfillment of this proposal will shred novel insight into the form and mechanism of PCD of CD4+T cells in sepsis, and provide preliminary basis for exploring novel therapeutic target for sepsis-induced immunosuppression.

脓毒症是严重创伤、感染和大手术患者常见并发症，免疫抑制和继发感染是脓毒症患者主要死亡原因。既往研究认为，凋亡是脓毒症CD4+T细胞死亡的主要形式，是脓毒症免疫抑制的关键机制。申请者前期研究发现，小鼠严重脓毒症模型中存在CD4+T细胞焦亡；尼克酰磷酸核糖转移酶（NAMPT）抑制剂FK866可减少CD4+T细胞焦亡，修复小鼠T细胞功能。本项目提出研究假设：NAMPT通过调控CD4+T细胞焦亡参与脓毒症免疫抑制的发生。本项目拟：1.研究创伤脓毒症患者血浆NAMPT水平与CD4+T细胞焦亡的关系及临床意义；2.观察NAMPT对脓毒症CD4+T细胞焦亡的影响；3.进一步探讨NAMPT调控对脓毒症CD4+T细胞焦亡的分子机制。本项目将为认识脓毒症免疫抑制发生机制提供新视角，并为脓毒症免疫抑制的治疗提供新的靶点。

脓毒症是严重创伤、感染和大手术患者常见并发症，免疫抑制和继发感染是脓毒症患者主要死亡原因。在本基金项目的支持下，课题组主要进行了以下的研究：1.研究了脓毒症中淋巴细胞焦亡的发生规律，并阐明了其在脓毒症发生发展的作用及相关机制；2.探索了NAMPT在严重创伤和脓毒症的相关病理和免疫紊乱中的作用，并阐述了相关机制；3.以细胞焦亡及NAMPT为治疗靶点，探索了其在脓毒症及相关并发症中的治疗效果。结果发现：依赖caspase-1的T淋巴细胞焦亡是严重创伤及脓毒症发生免疫紊乱的重要机制，并且与脓毒症的不良预后相关。发现脓毒症患者NAMPT血浆水平与T淋巴细胞焦亡显著相关，NAMPT抑制剂（FK866）能够抑制T淋巴细胞焦亡，同时，FK866通过上调脾脏中Sirt-6的表达、抑制NF-κB，减轻小鼠全身炎性细胞因子风暴，改善脓毒症免疫紊乱，并改善脓毒症预后。此外，发现NAMPT抑制剂（FK866）通过抑制c-jun-N-terminal kinase通路促进细胞自噬，改善脓毒症诱导的ALI，对脓毒症具有保护作用。总之，课题组的研究成果不仅对脓毒症的病理生理和免疫失衡等关键问题的认识提供了新的视角，并且为脓毒症及相关并发症的治疗提供了新的策略。