HMGB1内化诱导的巨噬细胞焦亡（pyroptosis）在脓毒症中的作用和意义

Sepsis is a clinical syndrome that complicates severe infection and is characterized by the systemic inflammatory response syndrome (SIRS). Macrophages are found in essentially all tissues. They play a critical role in the beginning of inflammation, and also exist in the late phase of sepsis. Macrophages can be activated and regulated by high-mobility group box 1 (HMGB1), an important late phase inflammatory mediator. In our previous study, we identified a novel pathway of HMGB1-induced macrophage pyroptosis. We demonstrated that HMGB1, acting through RAGE and dynamin-dependent signaling, initiates HMGB1endocytosis, which in turn induces caspase-1 activation and cell pyroptosis. Pyroptosis is a caspase-1-dependent programmed cell death, which can be triggered by various stimuli. We further confirm that HMGB1-induced macrophage pyroptosis also occurs in vivo during late endotoxemia, suggesting a pathophysiological significance for this form of pyroptosis in the development of inflammation. However, the function of macrophage pyroptosis remains unclear. In this study, firstly, we plan to exam the inflammatory responses of pyroptosis macrophages which were induced by HMGB1 and found in sepsis mice. Then the macrophages of sepsis mice will be replaced by pyroptosis macrophages which were induced by HMGB1. These works will figure out the functions and the fates of macrophages in late inflammation and sepsis, which may be very important for the treatment of SIRS and sepsis.

脓毒症是由感染引起的全身炎症反应综合征，病情凶险，病死率高。巨噬细胞是免疫系统的重要组成，在全身炎症反应的发生发展全过程中都发挥至关重要作用。然而巨噬细胞对脓毒症晚期炎症反应程度和病情预后的影响及其机制目前还不完全清楚。本课题组发现，脓毒症晚期重要炎症介质HMGB1可以被巨噬细胞内化，在12 h后激活蛋白水解酶caspase-1，促进细胞发生焦亡pyroptosis。后者是新发现的一种巨噬细胞死亡方式，是炎症相关的生物学过程，但其作用和意义还不清楚。推测巨噬细胞可能通过焦亡过程对脓毒症晚期炎症水平和病情预后产生重要影响。本课题设计分别以体外诱导的焦亡巨噬细胞、晚期脓毒症小鼠体内的焦亡细胞、被焦亡巨噬细胞替换的脓毒症小鼠为研究对象，探索HMGB1内化诱导的巨噬细胞焦亡过程在脓毒症晚期炎症反应中的作用和意义，从而对临床脓毒症晚期患者的病情控制具有积极的指导意义。