Department of Anesthesiology and Intensive Care Medicine, Molecular Intensive Care Medicine, University Hospital Eberhard-Karls University, 72076 Tübingen, Germany.
Hertie Institute for Clinical Brain Research, University Clinic Tübingen, 72076 Tübingen, Germany.
Proc Natl Acad Sci U S A. 2021 Mar 2;118(9). doi: 10.1073/pnas.2017527118.
Endogenous mediators regulating acute inflammatory responses in both the induction and resolution phases of inflammatory processes are pivotal in host defense and tissue homeostasis. Recent studies have identified neuronal guidance proteins characterized in axonal development that display immunomodulatory functions. Here, we identify the neuroimmune guidance cue Semaphorin 7A (Sema7A), which appears to link macrophage (MΦ) metabolic remodeling to inflammation resolution. Sema7A orchestrated MΦ chemotaxis and chemokinesis, activated MΦ differentiation and polarization toward the proresolving M2 phenotype, and promoted leukocyte clearance. Peritoneal MΦ displayed metabolic reprogramming, characterized by reductions in fatty acid oxidation and oxidative phosphorylation, increases in glycolysis and the pentose phosphate pathway, and truncation of the tricarboxylic acid cycle, which resulted in increased levels of the intermediates succinate and fumarate. The low accumulation of citrate in MΦ correlated with the decreased synthesis of prostaglandins, leading to a reduced impact on lipid-mediator class switching and the generation of specialized pro resolving lipid mediators. Signaling network analysis indicated that Sema7A induced the metabolic reprogramming of MΦ by activating the mTOR- and AKT2-signaling pathways. Administration of Sema7A orchestrated the resolution response to tissue homeostasis by shortening the resolution interval, promoting tissue protection in murine peritonitis, and enhancing survival in polymicrobial sepsis.
内源性介质在炎症过程的诱导和消退阶段调节急性炎症反应，在宿主防御和组织动态平衡中起着关键作用。最近的研究已经确定了在轴突发育中具有特征的神经免疫导向蛋白，这些蛋白具有免疫调节功能。在这里，我们鉴定了神经免疫导向因子 Sema7A（Semaphorin 7A），它似乎将巨噬细胞（MΦ）代谢重塑与炎症消退联系起来。Sema7A 协调 MΦ 的趋化和趋动，激活 MΦ 的分化和向促消退的 M2 表型极化，并促进白细胞清除。腹膜 MΦ 表现出代谢重编程，其特征是脂肪酸氧化和氧化磷酸化减少，糖酵解和戊糖磷酸途径增加，三羧酸循环缩短，导致中间产物琥珀酸和富马酸水平增加。MΦ 中柠檬酸的低积累与前列腺素合成减少相关，导致对脂质介质类转换的影响降低，并产生专门的促消退脂质介质。信号网络分析表明，Sema7A 通过激活 mTOR 和 AKT2 信号通路诱导 MΦ 的代谢重编程。Sema7A 的给药通过缩短缓解间隔来协调组织动态平衡的缓解反应，促进小鼠腹膜炎中的组织保护，并提高多微生物脓毒症中的存活率。
