巨噬细胞LPS恢复的代谢基础

当机体受到病原菌的轻微感染时，巨噬细胞会被激活并协调炎症反应从而启动宿主防御；然而严重的感染会导致巨噬细胞进入耐受状态。这种耐受状态可以通过抑制免疫反应来保护机体免受持续性炎症导致的组织损伤，但也会增加机体对机会感染的易感性并削弱机体对后续感染的宿主防御能力。因此，巨噬细胞耐受持续时间的正确调控对于人类的生命安全至关重要。我们的前期研究发现：AKT-mTORC1通路以及线粒体代谢的增强促进巨噬细胞激活，而减弱则促进巨噬细胞耐受。据此我们提出：AKT-mTORC1通路以及线粒体代谢的恢复构成巨噬细胞恢复的代谢基础。在本研究计划中，我们将详细阐明巨噬细胞的恢复过程及其中AKT-mTORC1通路和线粒体恢复的机制，并最终明确该通路是否、以及怎样参与调控巨噬细胞炎症应答能力的恢复。我们的研究有望为治疗性调控巨噬细胞功能提供理论基础，并为败血症及其他炎症反应失调、免疫抑制相关疾病的治疗提供新的思路。

During a limited microbial infection, macrophages become activated to coordinate inflammatory responses that mediate host defense, while overwhelming infection drives activated macrophages to a tolerant state that orchestrates suppression of inflammatory responses to protect against tissue damage. However, prolonged macrophage tolerance is detrimental in sepsis and a plethora of sepsis-associated diseases, increasing susceptibility to opportunistic pathogens and/or impairing host defense to subsequent infections. Careful regulation of the duration of macrophage tolerance is thus critical, but nothing is known of how macrophages could recover from tolerance to regain responsive to microbial exposure. Here, building on our previous work that increased AKT-mTORC1 signaling and mitochondrial metabolism drive macrophage activation while decreased AKT-mTORC1 signaling and mitochondrial metabolism contribute to macrophage tolerance, we propose that recovery of AKT-mTORC1 signaling and mitochondrial metabolism constitute a metabolic cornerstone of macrophage recovery. We will comprehensively characterize the process of macrophage recovery, including recovery of AKT-mTORC1 activity, mitochondrial metabolism, and ability to induce inflammatory responses. We will determine the mechanistic basis of AKT-mTORC1 recovery and mitochondrial recovery. Finally, we will determine if and how AKT-mTORC1 recovery and mitochondrial recovery regulate the ability to re-induce inflammatory responses in recovered macrophages. By elucidating the fundamental basis of macrophage recovery, our proposed study should open new therapeutic windows in the modulation of sepsis and other diseases characterized by dysregulated inflammation and immunosuppression.