FOXO3A抑制Kupffer细胞中STAT1/c-FLIP轴介导的坏死性凋亡途径调控机体内毒素耐受

Kupffer细胞（KCs）内毒素耐受是机体限制内毒素休克的重要保护机制。目前认为，诱导KCs内毒素耐受的主要机制是抑制NF-κB的活化，现有报道称抑制细胞坏死性凋亡途径后可抑制NF-κB介导的炎症反应，但并无文献报道此途径是否参与诱导KCs内毒素耐受，机制也尚不可知。而据国内外研究发现，细胞凋亡抑制蛋白（c-FLIP）是促进LPS介导巨噬细胞坏死性凋亡的正向调控因子，FOXO3A则可通过抑制c-FLIP的转录因子STAT1的DNA定位，下调c-FLIP的表达。因此，我们推测FOXO3A通过抑制STAT1/c-FLIP信号轴，负性调控坏死性凋亡途径，诱导KCs内毒素耐受。本项目选择KCs为靶细胞，以FOXO3A-STAT1/c-FLIP为研究轴线，探讨坏死性凋亡途径是否参与调控KCs内毒素耐受，以及其确切机制，为治疗炎症相关性疾病提供新的思路。

Endotoxin tolerance induced by Kupffer cells (KCs) is an important protective mechanism for limiting the endotoxin shock. The accepted main mechanism to induce the endotoxin tolerance of KCs is to inhibit the activation of NF-κB. It is reported that inhibition of cellular necroptosis can relieve the inflammatory response mediated by nuclear factor kappa B (NF-κB). However, it has not been studied whether inhibition of cellular necroptosis can induce the endotoxin tolerance of KCs, and its mechanism is still a mystery. Recent findings assert that cellular FLICE-inhibitory protein (c-FLIP) is a positive regulatory factor which promotes necroptosis induced by LPS in macrophages. In addition, FOXO3A down-regulates the expression of c-FLIP by inhibiting the DNA location of signal transducer and activator of transcription 1 (STAT1), which is the main transfer factor of c-FLIP. Thus, it is reasonable to assume FOXO3A can induce endotoxin tolerance of KCs through negatively regulating necroptosis via STAT1/c-FLIP axis. In this study, we will focus on the KCs and take FOXO3A-STAT1/c-FLIP axis as the leading clue, to explore the effects of necroptosis on endotoxin tolerance. We hope these works could provide a novel idea for the treatment of inflammation-related diseases.