Macrophage immunometabolism controls septic shock

炎症的进化导致了无菌或微生物损伤的恢复。炎症过程的诱导不仅激活了免疫细胞，还改变了它们的新陈代谢，从而形成了免疫反应。越来越多的证据表明，正确的炎症过程需要模式识别受体(PRRs)对外源性病原体相关分子模式(PAMPs)和内源性损伤相关分子模式(DAMP)的一致识别。我们最近证实，革兰氏阴性菌的主要成分脂多糖和宿主来源的氧化磷脂(OxPAPC)的一致识别导致吞噬细胞的形成，其特征是一种独特的代谢特征，增加了一种强大的促炎细胞因子白介素1β的产生。内毒素和oxPAPC的同时相遇是否以及如何改变吞噬细胞的其他炎症活动在很大程度上尚不清楚。基于新的令人信服的数据，我们假设，内毒素和oxPAPC的一致识别改变了关键的代谢检查点，从而驱动了炎症。此外，这些变化可以用来预防感染性休克。脓毒症是一种复杂的炎症综合征，其特征是一种称为败血症休克的高炎症期。尽管之前有人提出oxPAPC通过抑制内毒素的信号传递能力来保护脓毒症的高炎性阶段，但我们新的未发表的数据表明，oxPAPC的产生跟随着体内的内毒素或细菌接触，并且oxPAPC增加了脓毒症小鼠模型的炎症和致死性。值得注意的是，我们发现，为了发挥其功能，oxPAPC直接与AKT相互作用并抑制AKT。AKT是一个中央代谢检查点，调节吞噬细胞的新陈代谢和炎症活动。OxPAPC抑制AKT可阻止IL-10的产生。IL-10是一种多能的免疫调节细胞因子，在脓毒症过程中维持免疫稳态和抑制炎症是不可或缺的。机制上，oxPAPC依赖的对AKT的抑制增强了蛋氨酸循环，有利于组蛋白H3的三甲基化，从而关闭了IL-10转录。在我们新的可靠数据的支持下，我们将利用生化、转录和表观遗传学分析，以及体外代谢组学来进一步剖析脂多糖遭遇过程中oxPAPC启动的信号级联反应。通过使用新的转基因或条件基因敲除小鼠，以及商业上可用的药物，我们将在体内测试针对新发现的由oxPAPC调节的代谢途径以预防败血症的可能性。总之，我们将描述介导宿主来源的炎性配体依赖的免疫代谢功能的分子成分。我们的研究将为调节免疫系统激活和脓毒症提供潜在的治疗靶点，脓毒症是一种在西方国家普遍存在的破坏性炎症综合征。

Inflammation evolved to lead to recovery from sterile or microbial injuries. The induction of the inflammatory process not only activates the immune cells, but also alters their metabolism and thus forge the immune response. Accumulating evidence shows that a proper inflammatory process requires the coincident recognition by pattern recognition receptors (PRRs) of exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs). We recently demonstrated that the coincident recognition of lipopolysaccharide (LPS), the major component of Gram-negative bacteria, and host-derived oxidized phospholipids known as oxPAPC (a class of DAMPs) leads to the formation of phagocytes characterized by a unique metabolic profile that increases the production of interleukin (IL)-1β, a potent pro-inflammatory cytokine. Whether, and how, the simultaneous encounter of LPS and oxPAPC alters other inflammatory activities of phagocytes remains largely unknown. Based on new compelling data, here we hypothesize that the coincident recognition of LPS and oxPAPC alters key metabolic checkpoints to drive hyper-inflammation. Also, that these changes can be harnessed against septic shock. Sepsis is a complex inflammatory syndrome characterized by a hyper-inflammatory phase called septic shock. Although it was previously proposed that oxPAPC protects against the hyperinflammatory phase of sepsis by inhibiting the capacity of LPS to signal, our new unpublished data show instead that oxPAPC production follows LPS or bacterial encounter in vivo and that oxPAPC increases inflammation and lethality in mouse models of sepsis. Notably, we found that, to exert its functions, oxPAPC directly interacts with, and inhibits, AKT. AKT is a central metabolic checkpoint that regulates the metabolism of phagocytes and their inflammatory activity. AKT inhibition by oxPAPC prevents the production of IL-10. IL-10 is a pluripotent immunoregulatory cytokine indispensable for maintaining immune homeostasis and restricting inflammation during sepsis. Mechanistically, oxPAPC-dependent inhibition of AKT potentiates the methionine cycle and favors the trimethylation of the histone H3, thus switching off IL-10 transcription. Supported by our new solid data, we will employ biochemistry, transcriptional and epigenetic analyses, as well as metabolomics in vitro to further dissect the signaling cascade initiated by oxPAPC during LPS encounter. By using new transgenic or conditional knock-out mice, as well as commercially available drugs, we will test in vivo the possibility to target the newly identified metabolic pathways regulated by oxPAPC to protect against sepsis. Altogether we will characterize the molecular components that mediate host-derived inflammatory ligand-dependent immunometabolic functions. Our study will offer potential therapeutic targets for modulating immune system activation and sepsis, a devastating inflammatory syndrome that is widespread in western countries.