Kupffer细胞（KCs）内毒素耐受的发生与NF-κB活性的可塑性密切相关，而NF-κB可通过影响细胞能量代谢方式诱导KCs表型重塑。现有报道称，TBK1对NF-κB的活性具有双重的调控作用，但具体原因不清楚。文献报道及课题组前期发现，TBK1与其上游p38α/c-Myb-DTX4通路形成负反馈弧，调控LPS诱导的炎症反应；TBK1亦可通过磷酸化RIPK1/RIPK3复合体调控谷氨酰胺的分解代谢，诱导KCs表型重塑，限制机体炎症反应。因此，我们推测p38α/c-Myb-TBK1负反馈弧可能通过RIPK1/RIPK3复合体-谷氨酰胺代谢途径诱导KCs表型重塑，参与调控内毒素耐受。本项目将以KCs为靶细胞，TBK1为切入点，探讨p38α/c-Myb-TBK1负反馈弧是否可通过谷氨酰胺代谢途径参与调控KCs内毒素耐受及其确切机制，为临床上治疗内毒素休克等相关炎症性疾病提供新的思路。

The endotoxin tolerance of Kupffer cells (KCs) is closely related to the plasticity of nuclear transcription factor kappa B (NF-κB), which induces the phenotype remodeling of KCs via influencing the cellular energy metabolism. It is reported that TANK-binding kinase 1 (TBK1) has a dual regulatory effect on activation of NF-κB, but the reason is not clear. Recent reports and our previous works have found that TBK1 and its upstream pathway of p38α/c-Myb-deltex E3 ubiquitin ligase 4 (DTX4) form a negative feedback arc, which regulates the endotoxin-induced inflammatory response. In addition, TBK1 regulates the glutamine metabolism by phosphorylating the receptor-interacting serine/threonine-protein kinase 1 (RIPK1)/RIPK3 complex, further leading the phenotypic remodeling of KCs and limiting inflammatory responses. Thus, it is reasonable to assume p38α/c-Myb-TBK1 negative feedback arc regulates endotoxin tolerance through inducing the phenotypic remodeling of KCs via RIPK1/RIPK3 complex-glutamine metabolism pathway. In this study, we will focus on the KCs and take TBK1 as the leading perspective, to explore the effects of p38α/c-Myb-TBK1 negative feedback arc on endotoxin tolerance. We hope these works could provide a novel idea for the treatment of endotoxin shock and other inflammation-related diseases.