mTOR/HIF1α-mediated aerobic glycolysis as metabolic basis for trained immunity

• Published in: Science (American Association for the Advancement of Science) Vol. 345; no. 6204; p. 1250684
• Main Authors: Cheng, Shih-Chin, Quintin, Jessica, Cramer, Robert A., Shepardson, Kelly M., Saeed, Sadia, Kumar, Vinod, Giamarellos-Bourboulis, Evangelos J, Martens, Joost H.A., Rao, Nagesha Appukudige, Aghajanirefah, Ali, Manjeri, Ganesh R., Li, Yang, Ifrim, Daniela C., Arts, Rob J.W., van der Meer, Brian M.J.W., Deen, Peter M.T., Logie, Colin, O’Neill, Luke A., Willems, Peter, van de Veerdonk, Frank L., van der Meer, Jos W.M., Ng, Aylwin, Joosten, Leo A.B., Wijmenga, Cisca, Stunnenberg, Hendrik G., Xavier, Ramnik J., Netea, Mihai G.
• Format: Journal Article
• Language: English
• Published: 26-09-2014
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1250684

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.