Sema7A is crucial for resolution of severe inflammation.
Sema7A is crucial for resolution of severe inflammation.
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DOI：
10.1073/pnas.2017527118
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发表时间：
2021-03-02
影响因子：
11.1
通讯作者：
Mirakaj V
中科院分区：
文献类型：
--
作者：
Körner A;Bernard A;Fitzgerald JC;Alarcon-Barrera JC;Kostidis S;Kaussen T;Giera M;Mirakaj V
未消退的炎症是脓毒症和/或多器官衰竭的标志，仍然是医学上的一个挑战。死亡率是巨大的，迄今为止没有足够的治疗方法。在这里，我们确定了一个以前未被认识到的作用，神经元的指导蛋白semaphorin 7A在过渡到解决过程中严重的系统性炎症，如败血症。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，在宿主防御和组织稳态中起关键作用。最近的研究已经确定了神经元的指导蛋白，其特征在于轴突的发展，显示免疫调节功能。在这里，我们确定了神经免疫导向因子Semaphorin 7A（Sema 7A），它似乎将巨噬细胞（MΦ）代谢重塑与炎症消退联系起来。Sema 7A协调MΦ趋化性和趋化运动，激活MΦ分化和向前解M2表型极化，并促进白细胞清除。腹膜MΦ Sema 7A-/-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，以及三羧酸循环截短，从而导致中间产物琥珀酸和富马酸水平增加。MΦ Sema 7A-/-中柠檬酸盐的低积累与前列腺素合成的减少相关，导致对脂质介体类别转换和专门的促分解脂质介体的产生的影响降低。信号网络分析表明Sema 7A通过激活mTOR和AKT 2信号通路诱导MΦ的代谢重编程。施用Sema 7ASL 4cd通过缩短消退间隔、促进鼠腹膜炎中的组织保护和增强多微生物败血症中的存活来协调对组织稳态的消退响应。
Nonresolving inflammation, a hallmark of sepsis and/or multi-organ failure, still poses a challenge in medicine. The mortality rate is enormous, and so far no adequate curative therapy is available. Here we identify a previously unrecognized role of the neuronal guidance protein semaphorin 7A in the transition to resolution processes in severe systematic inflammation such as sepsis. 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 MΦSema7A−/− 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 MΦSema7A−/− 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 Sema7ASL4cd orchestrated the resolution response to tissue homeostasis by shortening the resolution interval, promoting tissue protection in murine peritonitis, and enhancing survival in polymicrobial sepsis.
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DOI：
10.1084/jem.20132103
发表时间：
2014-06-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Mirakaj V;Dalli J;Granja T;Rosenberger P;Serhan CN
通讯作者：
Serhan CN
影响因子：
32.4
作者：
Czopik, Agnieszka K.;Bynoe, Margaret S.;Medzhitov, Ruslan
通讯作者：
Medzhitov, Ruslan
影响因子：
32.4
作者：
Buckley, Christopher D.;Gilroy, Derek W.;Serhan, Charles N.
通讯作者：
Serhan, Charles N.
DOI：
10.1084/jem.20151570
发表时间：
2016-01-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
O'Neill LA;Pearce EJ
通讯作者：
Pearce EJ
影响因子：
7.8
作者：
Covarrubias AJ;Aksoylar HI;Horng T
通讯作者：
Horng T