免疫麻痹是脓毒症死亡的主要原因之一，但机制不明。免疫细胞有氧糖酵解受损、促炎因子分泌能力下降是免疫麻痹的重要特征。我们前期发现免疫麻痹时TNF-α表达、有氧糖酵解调节蛋白mTOR活性降低，单核细胞的负向调控模式识别受体NLRC3表达升高。由于NLRC3可通过结合PI3K来调节mTOR活性及调控TRAF6 K63位泛素化，因此，我们提出研究假设：NLRC3上调造成PI3K-mTOR介导氧糖酵解及TRAF6 K63位泛素化介导的促炎信号受损，从而导致脓毒症免疫麻痹。本项目拟开展以下研究工作：首先，探讨NLRC3在脓毒症免疫麻痹进程中的表达变化。其次，研究NLRC3对脓毒症免疫麻痹及其有氧糖酵解的影响；然后，探讨NLRC3与mTOR信号通路相互作用及关系；最后，探讨NLRC3与TRAF6信号通路相互作用及关系；本研究将有助于深入认识脓毒症免疫麻痹的发生机制，为改善免疫麻痹提供新的分子靶点。

Sepsis-induced immunoparalysisis is a leading cause of death for septic patients, but the mechanism remains to be identied. The impaired aerobic glycolysis (Warburg effect) and the downregulated ability of proinflammatory cytokines production are the main features in these patients who encountered immunoparalysis. Our preliminary study showed that the release of TNF-α, the activation of mTOR which is involved in the anaerobic glycolysis were decreased in the immune cells from septic immunoparalysis. At the same time, we found the mRNA expression of NLRC3 was increased which is a pattern recognition receptor related to negatively regulate the host response in monocytes from the hyporeactive septic patients. The NLRC3 could reduce the activity of PI3K p85 itself involved in the activation of mTOR pathway and inhibit the k63-linked polyubiquitination of TRAF6 involved in the activation of NF-κB p65. According these findings we hypothesize that NLRC3 promote immunoparalysis via inhibiting the PI3K-mTOR signaling pathway mediated the Warburg effect and dampening TRAF6 ubiquitination mediated the NF-κB p65 activation in sepsis. We will thus test this hypothesis in present proposal as follow. Aim1, we will observe the change of NLRC3 in human monocytes and mice splenic cells or monocytes/macrophages during the progression of immunoparalysis. Aim2, we are also going to investigate the effects of NLRC3 on the glycolysis and immunoparalysis of sepsis. Aim3, the interaction of NLRC3 and mTOR pathway will be studied, and we will conform that mTOR pathway is a downstream molecular of NLRC3. Aim4, the interaction of NLRC3 and TRAF6 pathway will be investigated, and we will further conform that TRAF6 pathway is a downstream molecular of NLRC3. This research may helpful to further clarify the mechanism of septic immunoparalysis and provide a new molecular target to rescue immunoparalysis.