mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity.
mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity.
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DOI：
10.1126/science.1250684
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发表时间：
2014-09-26
期刊：
影响因子：
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通讯作者：
Netea MG
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文献类型：
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作者：
Cheng SC;Quintin J;Cramer RA;Shepardson KM;Saeed S;Kumar V;Giamarellos-Bourboulis EJ;Martens JH;Rao NA;Aghajanirefah A;Manjeri GR;Li Y;Ifrim DC;Arts RJ;van der Veer BM;Deen PM;Logie C;O'Neill LA;Willems P;van de Veerdonk FL;van der Meer JW;Ng A;Joosten LA;Wijmenga C;Stunnenberg HG;Xavier RJ;Netea MG
通过感染或疫苗接种对骨髓细胞进行表观遗传重编程，称为训练免疫，赋予非特异性保护免受继发感染。我们表征了用β-葡聚糖训练的人单核细胞的全基因组转录组和组蛋白修饰谱，并鉴定了参与葡萄糖代谢的基因的诱导表达。经过训练的单核细胞显示出高葡萄糖消耗、乳酸产生和NAD+/NADH比率，反映出经过训练的单核细胞的代谢发生变化，糖酵解增加依赖于通过dectin-1/Akt/HIF 1 α途径激活哺乳动物雷帕霉素靶标（mTOR）。抑制Akt、mTOR或HIF 1 α可阻断单核细胞对训练免疫的诱导，而AMPK激活剂二甲双胍可抑制对真菌感染的先天免疫应答。最后，具有骨髓细胞特异性缺陷的小鼠HIF 1 α不能对细菌性脓毒症产生训练过的免疫力。总之，Akt/mTOR/HIF 1 α依赖性诱导有氧糖酵解代表了训练免疫的代谢基础。
Epigenetic reprogramming of myeloid cells by infection or vaccination, termed trained immunity, confers non-specific protection from secondary infections. We characterized genome-wide transcriptome and histone modification profiles of human monocytes trained with β-glucan and identified induced expression of genes involved in glucose metabolism. Trained monocytes display high glucose consumption, lactate production, and NAD+/NADH ratio, reflecting a shift in the metabolism of trained monocytes with an increase in glycolysis dependent on the activation of mammalian target of rapamycin (mTOR) through a dectin-1/Akt/HIF1α pathway. Inhibition of Akt, mTOR, or HIF1α blocked monocyte induction of trained immunity, whereas the AMPK activator metformin inhibited the innate immune response to fungal infection. Finally, mice with a myeloid cell-specific defect in HIF1α were unable to mount trained immunity against bacterial sepsis. In conclusion, Akt/mTOR/HIF1α-dependent induction of aerobic glycolysis represents the metabolic basis of trained immunity.
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影响因子：
64.5
作者：
Chang CH;Curtis JD;Maggi LB Jr;Faubert B;Villarino AV;O'Sullivan D;Huang SC;van der Windt GJ;Blagih J;Qiu J;Weber JD;Pearce EJ;Jones RG;Pearce EL
通讯作者：
Pearce EL
影响因子：
16.8
作者：
Kurtz, J
通讯作者：
Kurtz, J
影响因子：
20.3
作者：
Everts, Bart;Amiel, Eyal;Pearce, Edward J.
通讯作者：
Pearce, Edward J.
影响因子：
4.8
作者：
Liu, Tie Fu;Vachharajani, Vidula T.;McCall, Charles E.
通讯作者：
McCall, Charles E.
DOI：
10.1038/nri3198
发表时间：
2012-04-20
期刊：
Nature reviews. Immunology
影响因子：
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作者：
通讯作者：
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