Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity.
Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity.
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DOI：
10.1016/j.cmet.2016.10.008
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发表时间：
2016-12-13
期刊：
影响因子：
29
通讯作者：
Netea MG
中科院分区：
文献类型：
--
作者：
Arts RJ;Novakovic B;Ter Horst R;Carvalho A;Bekkering S;Lachmandas E;Rodrigues F;Silvestre R;Cheng SC;Wang SY;Habibi E;Gonçalves LG;Mesquita I;Cunha C;van Laarhoven A;van de Veerdonk FL;Williams DL;van der Meer JW;Logie C;O'Neill LA;Dinarello CA;Riksen NP;van Crevel R;Clish C;Notebaart RA;Joosten LA;Stunnenberg HG;Xavier RJ;Netea MG
训练免疫（先天免疫记忆）的诱导是通过激活免疫和代谢途径介导的，这些途径导致细胞功能程序的表观遗传重新布线。通过转录组学和代谢组学数据的网络水平整合，我们确定糖酵解、谷氨酰胺解和胆固醇合成途径对于β-葡聚糖在单核细胞中诱导训练免疫是不可或缺的。由于TCA循环中谷氨酰胺的补充，富马酸的积累整合了免疫和代谢回路，通过抑制KDM5组蛋白去甲基化酶诱导单核细胞表观遗传重编程。此外，富马酸盐本身诱导了类似于β-葡聚糖诱导的训练免疫的表观遗传程序。与此一致，抑制小鼠谷氨酰胺解和胆固醇合成降低了β-葡聚糖对训练免疫的诱导。识别导致训练免疫诱导的代谢途径有助于我们对先天免疫记忆的理解，并开辟新的治疗途径。
Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by β-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases. Furthermore, fumarate itself induced an epigenetic program similar to β-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by β-glucan. Identification of the metabolic pathways leading to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues.
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影响因子：
30.3
作者：
Quintin J;Saeed S;Martens JHA;Giamarellos-Bourboulis EJ;Ifrim DC;Logie C;Jacobs L;Jansen T;Kullberg BJ;Wijmenga C;Joosten LAB;Xavier RJ;van der Meer JWM;Stunnenberg HG;Netea MG
通讯作者：
Netea MG
影响因子：
64.8
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
影响因子：
32.4
作者：
O'Sullivan TE;Sun JC;Lanier LL
通讯作者：
Lanier LL
影响因子：
16.8
作者：
Kurtz, J
通讯作者：
Kurtz, J
影响因子：
14.9
作者：
SCHREIBER, E;HARSHMAN, K;FONTANA, A
通讯作者：
FONTANA, A