Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity

Rob J W Arts; Boris Novakovic; Rob ter Horst; Agostinho Carvalho; Siroon Bekkering; Ekta Lachmandas; Fernando Eduardo Rodrigues Ferreira; Ricardo Silvestre; Shih Chin Cheng; Shuang Yin Wang; Ehsan Habibi; Luis Pedro Goncalves; Inês Mesquita; Cristina Cunha; Arjan van Laarhoven; Frank L. van de Veerdonk; David L. Williams; Jos W M van der Meer; Colin Logie; Luke A. O'Neill; Charles A. Dinarello; Niels P. Riksen; Reinout van Crevel; Clary Clish; Richard A. Notebaart; Leo A B Joosten; Hendrik G. Stunnenberg; Ramnik J. Xavier; Mihai G. Netea

doi:10.1016/j.cmet.2016.10.008

Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity

Rob J W Arts, Boris Novakovic, Rob ter Horst, Agostinho Carvalho, Siroon Bekkering, Ekta Lachmandas, Fernando Eduardo Rodrigues Ferreira, Ricardo Silvestre, Shih Chin Cheng, Shuang Yin Wang, Ehsan Habibi, Luis Pedro Goncalves, Inês Mesquita, Cristina Cunha, Arjan van Laarhoven, Frank L. van de Veerdonk, David L. Williams, Jos W M van der Meer, Colin Logie, Luke A. O'NeillCharles A. Dinarello, Niels P. Riksen, Reinout van Crevel, Clary Clish, Richard A. Notebaart, Leo A B Joosten, Hendrik G. Stunnenberg, Ramnik J. Xavier, Mihai G. Netea

Research output: Contribution to journal › Article

233 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	807-819
Number of pages	13
Journal	Cell Metabolism
Volume	24
Issue number	6
DOIs	https://doi.org/10.1016/j.cmet.2016.10.008
Publication status	Published - 13 Dec 2016

Keywords

cholesterol metabolism
epigenetics
glutamine metabolism
glycolysis
trained immunity

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Arts, R. J. W., Novakovic, B., ter Horst, R., Carvalho, A., Bekkering, S., Lachmandas, E., Rodrigues Ferreira, F. E., Silvestre, R., Cheng, S. C., Wang, S. Y., Habibi, E., Goncalves, L. P., Mesquita, I., Cunha, C., van Laarhoven, A., van de Veerdonk, F. L., Williams, D. L., van der Meer, J. W. M., Logie, C., ... Netea, M. G. (2016). Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity. Cell Metabolism, 24(6), 807-819. https://doi.org/10.1016/j.cmet.2016.10.008

Arts, Rob J W ; Novakovic, Boris ; ter Horst, Rob ; Carvalho, Agostinho ; Bekkering, Siroon ; Lachmandas, Ekta ; Rodrigues Ferreira, Fernando Eduardo ; Silvestre, Ricardo ; Cheng, Shih Chin ; Wang, Shuang Yin ; Habibi, Ehsan ; Goncalves, Luis Pedro ; Mesquita, Inês ; Cunha, Cristina ; van Laarhoven, Arjan ; van de Veerdonk, Frank L. ; Williams, David L. ; van der Meer, Jos W M ; Logie, Colin ; O'Neill, Luke A. ; Dinarello, Charles A. ; Riksen, Niels P. ; van Crevel, Reinout ; Clish, Clary ; Notebaart, Richard A. ; Joosten, Leo A B ; Stunnenberg, Hendrik G. ; Xavier, Ramnik J. ; Netea, Mihai G. / Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity. In: Cell Metabolism. 2016 ; Vol. 24, No. 6. pp. 807-819.

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abstract = "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.",

keywords = "cholesterol metabolism, epigenetics, glutamine metabolism, glycolysis, trained immunity",

author = "Arts, {Rob J W} and Boris Novakovic and {ter Horst}, Rob and Agostinho Carvalho and Siroon Bekkering and Ekta Lachmandas and {Rodrigues Ferreira}, {Fernando Eduardo} and Ricardo Silvestre and Cheng, {Shih Chin} and Wang, {Shuang Yin} and Ehsan Habibi and Goncalves, {Luis Pedro} and In{\^e}s Mesquita and Cristina Cunha and {van Laarhoven}, Arjan and {van de Veerdonk}, {Frank L.} and Williams, {David L.} and {van der Meer}, {Jos W M} and Colin Logie and O'Neill, {Luke A.} and Dinarello, {Charles A.} and Riksen, {Niels P.} and {van Crevel}, Reinout and Clary Clish and Notebaart, {Richard A.} and Joosten, {Leo A B} and Stunnenberg, {Hendrik G.} and Xavier, {Ramnik J.} and Netea, {Mihai G.}",

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Arts, RJW, Novakovic, B, ter Horst, R, Carvalho, A, Bekkering, S, Lachmandas, E, Rodrigues Ferreira, FE, Silvestre, R, Cheng, SC, Wang, SY, Habibi, E, Goncalves, LP, Mesquita, I, Cunha, C, van Laarhoven, A, van de Veerdonk, FL, Williams, DL, van der Meer, JWM, Logie, C, O'Neill, LA, Dinarello, CA, Riksen, NP, van Crevel, R, Clish, C, Notebaart, RA, Joosten, LAB, Stunnenberg, HG, Xavier, RJ & Netea, MG 2016, 'Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity', Cell Metabolism, vol. 24, no. 6, pp. 807-819. https://doi.org/10.1016/j.cmet.2016.10.008

Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity. / Arts, Rob J W; Novakovic, Boris; ter Horst, Rob; Carvalho, Agostinho; Bekkering, Siroon; Lachmandas, Ekta; Rodrigues Ferreira, Fernando Eduardo; Silvestre, Ricardo; Cheng, Shih Chin; Wang, Shuang Yin; Habibi, Ehsan; Goncalves, Luis Pedro; Mesquita, Inês; Cunha, Cristina; van Laarhoven, Arjan; van de Veerdonk, Frank L.; Williams, David L.; van der Meer, Jos W M; Logie, Colin; O'Neill, Luke A.; Dinarello, Charles A.; Riksen, Niels P.; van Crevel, Reinout; Clish, Clary; Notebaart, Richard A.; Joosten, Leo A B; Stunnenberg, Hendrik G.; Xavier, Ramnik J.; Netea, Mihai G.

In: Cell Metabolism, Vol. 24, No. 6, 13.12.2016, p. 807-819.

Research output: Contribution to journal › Article

TY - JOUR

T1 - Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity

AU - Arts, Rob J W

AU - Novakovic, Boris

AU - ter Horst, Rob

AU - Carvalho, Agostinho

AU - Bekkering, Siroon

AU - Lachmandas, Ekta

AU - Rodrigues Ferreira, Fernando Eduardo

AU - Silvestre, Ricardo

AU - Cheng, Shih Chin

AU - Wang, Shuang Yin

AU - Habibi, Ehsan

AU - Goncalves, Luis Pedro

AU - Mesquita, Inês

AU - Cunha, Cristina

AU - van Laarhoven, Arjan

AU - van de Veerdonk, Frank L.

AU - Williams, David L.

AU - van der Meer, Jos W M

AU - Logie, Colin

AU - O'Neill, Luke A.

AU - Dinarello, Charles A.

AU - Riksen, Niels P.

AU - van Crevel, Reinout

AU - Clish, Clary

AU - Notebaart, Richard A.

AU - Joosten, Leo A B

AU - Stunnenberg, Hendrik G.

AU - Xavier, Ramnik J.

AU - Netea, Mihai G.

PY - 2016/12/13

Y1 - 2016/12/13

N2 - 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.

AB - 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.

KW - cholesterol metabolism

KW - epigenetics

KW - glutamine metabolism

KW - glycolysis

KW - trained immunity

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DO - 10.1016/j.cmet.2016.10.008

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JO - Cell Metabolism

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