Schmidt Elyse A, Fee Brian E, Henry Stanley C, Nichols Amanda G, Shinohara Mari L, Rathmell Jeffrey C, MacIver Nancie J, Coers Jörn, Ilkayeva Olga R, Koves Timothy R, Taylor Gregory A
From the Departments of Molecular Genetics and Microbiology.
the Geriatric Research, Education, and Clinical Center, Durham Veterans Affairs Health Care System, Durham, North Carolina 27705, and.
J Biol Chem. 2017 Mar 17;292(11):4651-4662. doi: 10.1074/jbc.M116.770735. Epub 2017 Feb 1.
The immunity-related GTPases (IRGs) are a family of proteins that are induced by interferon (IFN)-γ and play pivotal roles in immune and inflammatory responses. IRGs ostensibly function as dynamin-like proteins that bind to intracellular membranes and promote remodeling and trafficking of those membranes. Prior studies have shown that loss of Irgm1 in mice leads to increased lethality to bacterial infections as well as enhanced inflammation to non-infectious stimuli; however, the mechanisms underlying these phenotypes are unclear. In the studies reported here, we found that uninfected Irgm1-deficient mice displayed high levels of serum cytokines typifying profound autoinflammation. Similar increases in cytokine production were also seen in cultured, IFN-γ-primed macrophages that lacked Irgm1. A series of metabolic studies indicated that the enhanced cytokine production was associated with marked metabolic changes in the Irgm1-deficient macrophages, including increased glycolysis and an accumulation of long chain acylcarnitines. Cells were exposed to the glycolytic inhibitor, 2-deoxyglucose, or fatty acid synthase inhibitors to perturb the metabolic alterations, which resulted in dampening of the excessive cytokine production. These results suggest that Irgm1 deficiency drives metabolic dysfunction in macrophages in a manner that is cell-autonomous and independent of infectious triggers. This may be a significant contributor to excessive inflammation seen in Irgm1-deficient mice in different contexts.
免疫相关鸟苷三磷酸酶（IRGs）是一类由干扰素（IFN）-γ诱导产生的蛋白质，在免疫和炎症反应中起关键作用。IRGs表面上起着类似发动蛋白的作用，可与细胞内膜结合，促进这些膜的重塑和运输。先前的研究表明，小鼠体内Irgm1缺失会导致对细菌感染的致死率增加，以及对非感染性刺激的炎症反应增强；然而，这些表型背后的机制尚不清楚。在本文报道的研究中，我们发现未感染的Irgm1缺陷小鼠表现出高水平的血清细胞因子，这是严重自身炎症的典型表现。在缺乏Irgm1的经IFN-γ预处理的培养巨噬细胞中也观察到类似的细胞因子产生增加。一系列代谢研究表明，细胞因子产生的增强与Irgm1缺陷巨噬细胞中的显著代谢变化有关，包括糖酵解增加和长链酰基肉碱的积累。将细胞暴露于糖酵解抑制剂2-脱氧葡萄糖或脂肪酸合酶抑制剂以扰乱代谢改变，这导致过度的细胞因子产生受到抑制。这些结果表明，Irgm1缺陷以细胞自主且独立于感染触发因素的方式驱动巨噬细胞中的代谢功能障碍。这可能是在不同情况下Irgm1缺陷小鼠中出现过度炎症的一个重要因素。
