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巨噬细胞富马酸盐水解酶抑制mtRNA介导的干扰素产生
2023-03-16 14:15

近日,爱尔兰都柏林圣三一大学Luke A. J. O’Neill等研究人员合作发现,巨噬细胞富马酸盐水解酶抑制mtRNA介导的干扰素产生。这一研究成果于2023年3月8日在线发表在国际学术期刊《自然》上。

利用无偏见的代谢组学和稳定的同位素辅助追踪,研究人员表明,在脂多糖刺激后,会诱发炎症天冬氨酸-精氨酸分流。在精氨酸琥珀酸酯合成酶(ASS1)表达量增加的支持下,该分流也导致了胞浆富马酸水平的增加和富马酸介导的蛋白质琥珀化。三羧酸循环酶富马酸水解酶(FH)的药物抑制和基因去除进一步增加了细胞内富马酸水平。线粒体呼吸也被抑制,线粒体膜电位增加。RNA测序和蛋白质组学分析表明,FH的抑制会产生强烈的炎症效应。值得注意的是,急性FH抑制会抑制白细胞介素-10的表达,从而导致肿瘤坏死因子的分泌增加,这种效应被富马酸所重现。

此外,FH抑制而非富马酸,通过线粒体RNA(mtRNA)释放和激活RNA传感器TLR7、RIG-I和MDA5的机制增加干扰素-β的产生。当FH在长期的脂多糖刺激后被抑制时,这种效应在内源性上得到了重现。来自系统性红斑狼疮患者的细胞也表现出FH的抑制,这表明这一过程在人类疾病中的潜在致病作用。因此,研究人员确定了FH在维持适当的巨噬细胞细胞因子和干扰素反应中的保护作用。

据悉,代谢重构是巨噬细胞效应功能的基础,但其中的机制仍未完全确定。

附:英文原文

Title: Macrophage fumarate hydratase restrains mtRNA-mediated interferon production

Author: Hooftman, Alexander, Peace, Christian G., Ryan, Dylan G., Day, Emily A., Yang, Ming, McGettrick, Anne F., Yin, Maureen, Montano, Erica N., Huo, Lihong, Toller-Kawahisa, Juliana E., Zecchini, Vincent, Ryan, Tristram A. J., Bolado-Carrancio, Alfonso, Casey, Alva M., Prag, Hiran A., Costa, Ana S. H., De Los Santos, Gabriela, Ishimori, Mariko, Wallace, Daniel J., Venuturupalli, Swamy, Nikitopoulou, Efterpi, Frizzell, Norma, Johansson, Cecilia, Von Kriegsheim, Alexander, Murphy, Michael P., Jefferies, Caroline, Frezza, Christian, ONeill, Luke A. J.

Issue&Volume: 2023-03-08

Abstract: Metabolic rewiring underlies the effector functions of macrophages1,2,3, but the mechanisms involved remain incompletely defined. Here, using unbiased metabolomics and stable isotope-assisted tracing, we show that an inflammatory aspartate–argininosuccinate shunt is induced following lipopolysaccharide stimulation. The shunt, supported by increased argininosuccinate synthase (ASS1) expression, also leads to increased cytosolic fumarate levels and fumarate-mediated protein succination. Pharmacological inhibition and genetic ablation of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) further increases intracellular fumarate levels. Mitochondrial respiration is also suppressed and mitochondrial membrane potential increased. RNA sequencing and proteomics analyses demonstrate that there are strong inflammatory effects resulting from FH inhibition. Notably, acute FH inhibition suppresses interleukin-10 expression, which leads to increased tumour necrosis factor secretion, an effect recapitulated by fumarate esters. Moreover, FH inhibition, but not fumarate esters, increases interferon-β production through mechanisms that are driven by mitochondrial RNA (mtRNA) release and activation of the RNA sensors TLR7, RIG-I and MDA5. This effect is recapitulated endogenously when FH is suppressed following prolonged lipopolysaccharide stimulation. Furthermore, cells from patients with systemic lupus erythematosus also exhibit FH suppression, which indicates a potential pathogenic role for this process in human disease. We therefore identify a protective role for FH in maintaining appropriate macrophage cytokine and interferon responses.

DOI: 10.1038/s41586-023-05720-6

Source: https://www.nature.com/articles/s41586-023-05720-6

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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