Macrophage fumarate hydratase restrains mtRNA-mediated interferon production.
Macrophage fumarate hydratase restrains mtRNA-mediated interferon production.
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DOI：
10.1038/s41586-023-05720-6
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发表时间：
2023-03
期刊：
影响因子：
64.8
通讯作者：
O'Neill, Luke A. J.
中科院分区：
文献类型：
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作者：
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;O'Neill, Luke A. J.
代谢重连是巨噬细胞效应功能的基础，但所涉及的机制仍未完全确定。在这里，利用无偏代谢组学和稳定同位素辅助示踪，我们发现脂多糖刺激后会诱导炎症性天冬氨酸-精氨酸琥珀酸分流。这种分流在精氨酸琥珀酸合酶 (ASS1) 表达增加的支持下，也会导致胞质富马酸水平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合酶 (FH) 的药理抑制和基因消除进一步增加了细胞内富马酸水平。线粒体呼吸也受到抑制，线粒体膜电位增加。 RNA 测序和蛋白质组学分析表明，FH 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分泌增加，富马酸酯也具有这种作用。此外，FH 抑制（而非富马酸酯）通过线粒体 RNA (mtRNA) 释放和 RNA 传感器 TLR7、RIG-I 和 MDA5 激活驱动的机制增加干扰素-β 的产生。当长时间脂多糖刺激后 FH 受到抑制时，这种效应会内源性地重现。此外，系统性红斑狼疮患者的细胞也表现出 FH 抑制，这表明该过程在人类疾病中具有潜在的致病作用。因此，我们确定了 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。
Metabolic rewiring underlies the effector functions of macrophages, 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.
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DOI：
10.1084/jem.20151876
发表时间：
2016-05-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Caielli S;Athale S;Domic B;Murat E;Chandra M;Banchereau R;Baisch J;Phelps K;Clayton S;Gong M;Wright T;Punaro M;Palucka K;Guiducci C;Banchereau J;Pascual V
通讯作者：
Pascual V
影响因子：
7.7
作者：
Blatnik, Matthew;Frizzell, Norma;Baynes, John W.
通讯作者：
Baynes, John W.
影响因子：
8.8
作者：
Kim, Sujin;Lee, Keonyong;Kim, Yoosik
通讯作者：
Kim, Yoosik
影响因子：
32.4
作者：
Eisenstein, Anna;Hilliard, Brandon K.;Pope, Scott D.;Zhang, Cuiling;Taskar, Pranali;Waizman, Daniel A.;Israni-Winger, Kavita;Tian, Hui;Luan, Harding H.;Wang, Andrew
通讯作者：
Wang, Andrew
影响因子：
64.8
作者：
Bambouskova M;Gorvel L;Lampropoulou V;Sergushichev A;Loginicheva E;Johnson K;Korenfeld D;Mathyer ME;Kim H;Huang LH;Duncan D;Bregman H;Keskin A;Santeford A;Apte RS;Sehgal R;Johnson B;Amarasinghe GK;Soares MP;Satoh T;Akira S;Hai T;de Guzman Strong C;Auclair K;Roddy TP;Biller SA;Jovanovic M;Klechevsky E;Stewart KM;Randolph GJ;Artyomov MN
通讯作者：
Artyomov MN