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

被引：718

作者：

Arts, Rob J. W. ^{[1
]}

Novakovic, Boris ^{[2
]}

ter Horst, Rob ^{[1
]}

Carvalho, Agostinho ^{[3
,4
]}

Bekkering, Siroon ^{[1
]}

Lachmandas, Ekta ^{[1
]}

Rodrigues, Fernando ^{[3
,4
]}

Silvestre, Ricardo ^{[3
,4
]}

Cheng, Shih-Chin ^{[1
,5
]}

Wang, Shuang-Yin ^{[2
]}

Habibi, Ehsan ^{[2
]}

Goncalves, Luis G. ^{[6
]}

Mesquita, Ines ^{[3
,4
]}

Cunha, Cristina ^{[3
,4
]}

van Laarhoven, Arjan ^{[1
]}

van de Veerdonk, Frank L. ^{[1
]}

Williams, David L. ^{[7
,8
]}

van der Meer, Jos W. M. ^{[1
]}

Logie, Colin ^{[2
]}

O'Neill, Luke A. ^{[9
]}

Dinarello, Charles A. ^{[1
,10
]}

Riksen, Niels P. ^{[1
]}

van Crevel, Reinout ^{[1
]}

Clish, Clary ^{[11
]}

Notebaart, Richard A. ^{[1
]}

Joosten, Leo A. B. ^{[1
]}

Stunnenberg, Hendrik G. ^{[2
]}

Xavier, Ramnik J. ^{[11
,12
,13
,14
]}

Netea, Mihai G. ^{[1
]}

机构：

[1] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 GA Nijmegen, Netherlands

[2] Radboud Univ Nijmegen, Fac Sci, Dept Mol Biol, NL-6525 HP Nijmegen, Netherlands

[3] Univ Minho, Sch Hlth Sci, Life & Hlth Sci Res Inst ICVS, P-4710057 Braga, Portugal

[4] ICVS 3Bs PT Govt Associate Lab, P-4806909 Braga, Portugal

[5] Natl Tsing Hua Univ, Inst Mol Med, Hsinchu 300, Taiwan

[6] Univ Nova Lisboa, Inst Tecnol Quim & Biol Antonio Xavier, P-2780157 Oeiras, Portugal

[7] East Tennessee State Univ, Quillen Coll Med, Dept Surg, Johnson City, TN 37604 USA

[8] East Tennessee State Univ, Ctr Inflammat Infect Dis & Immun, Johnson City, TN 37604 USA

[9] Trinity Coll Dublin, Trinity Biomed Sci Inst, Dublin 2, Ireland

[10] Univ Colorado Denver, Dept Med, Aurora, CO 80045 USA

[11] Broad Inst Harvard Univ & Massachusetts Inst Tech, Cambridge, MA 02142 USA

[12] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA

[13] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA

[14] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA

来源：

CELL METABOLISM | 2016年 / 24卷 / 06期

基金：

欧盟地平线“2020”; 澳大利亚国家健康与医学研究理事会;

关键词：

ENERGY-METABOLISM; AMINO-ACIDS; CELL; REINFECTION; INHIBITION; PROTECTION; INFECTION; MEMORY;

D O I：

10.1016/j.cmet.2016.10.008

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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 beta-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 beta-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by b-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.

引用

页码：807 / 819

页数：13

共 41 条

[1]

The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of Pathway/Genome Databases [J].

Caspi, Ron ;

Altman, Tomer ;

Billington, Richard ;

Dreher, Kate ;

Foerster, Hartmut ;

Fulcher, Carol A. ;

Holland, Timothy A. ;

Keseler, Ingrid M. ;

Kothari, Anamika ;

Kubo, Aya ;

Krummenacker, Markus ;

Latendresse, Mario ;

Mueller, Lukas A. ;

Ong, Quang ;

Paley, Suzanne ;

Subhraveti, Pallavi ;

Weaver, Daniel S. ;

Weerasinghe, Deepika ;

Zhang, Peifen ;

Karp, Peter D. .

NUCLEIC ACIDS RESEARCH, 2014, 42 (D1) :D459-D471

[2]

Tools and methods for studying the Drosophila JAK/STAT pathway [J].

Chen, Qian ;

Giedt, Michelle ;

Tang, Lingfeng ;

Harrison, Douglas A. .

METHODS, 2014, 68 (01) :160-172

[3]

Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis [J].

Cheng, Shih-Chin ;

Scicluna, Brendon P. ;

Arts, Rob J. W. ;

Gresnigt, Mark S. ;

Lachmandas, Ekta ;

Giamarellos-Bourboulis, Evangelos J. ;

Kox, Matthijs ;

Manjeri, Ganesh R. ;

Wagenaars, Jori A. L. ;

Cremer, Olaf L. ;

Leentjens, Jenneke ;

van der Meer, Anne J. ;

van de Veerdonk, Frank L. ;

Bonten, Marc J. ;

Schultz, Marcus J. ;

Willems, Peter H. G. M. ;

Pickkers, Peter ;

Joosten, Leo A. B. ;

van der Poll, Tom ;

Netea, Mihai G. .

NATURE IMMUNOLOGY, 2016, 17 (04) :406-+

[4]

mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity [J].

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. .

SCIENCE, 2014, 345 (6204) :1579-+

[5]

Metaboloepigenetics: Interrelationships between energy metabolism and epigenetic control of gene expression [J].

Donohoe, Dallas R. ;

Bultman, Scott J. .

JOURNAL OF CELLULAR PHYSIOLOGY, 2012, 227 (09) :3169-3177

[6]

Systemic Acquired Resistance: Turning Local Infection into Global Defense [J].

Fu, Zheng Qing ;

Dong, Xinnian .

ANNUAL REVIEW OF PLANT BIOLOGY, VOL 64, 2013, 64 :839-863

[7]

Dysregulated metabolism contributes to oncogenesis [J].

Hirschey, Matthew D. ;

DeBerardinis, Ralph J. ;

Diehl, Anna Mae E. ;

Drew, Janice E. ;

Frezza, Christian ;

Green, Michelle F. ;

Jones, Lee W. ;

Ko, Young H. ;

Le, Anne ;

Lea, Michael A. ;

Locasale, Jason W. ;

Longo, Valter D. ;

Lyssiotis, Costas A. ;

McDonnell, Eoin ;

Mehrmohamadi, Mahya ;

Michelotti, Gregory ;

Muralidhar, Vinayak ;

Murphy, Michael P. ;

Pedersen, Peter L. ;

Poore, Brad ;

Raffaghello, Lizzia ;

Rathmell, Jeffrey C. ;

Sivanand, Sharanya ;

Vander Heiden, Matthew G. ;

Wellen, Kathryn E. .

SEMINARS IN CANCER BIOLOGY, 2015, 35 :S129-S150

[8]

Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation [J].

Jiang, Yuhui ;

Qian, Xu ;

Shen, Jianfeng ;

Wang, Yugang ;

Li, Xinjian ;

Liu, Rui ;

Xia, Yan ;

Chen, Qianming ;

Peng, Guang ;

Lin, Shiaw-Yih ;

Lu, Zhimin .

NATURE CELL BIOLOGY, 2015, 17 (09) :1158-+

[9]

Hypoxia-inducible factor-1 (HIF-1) [J].

Ke, Qingdong ;

Costa, Max .

MOLECULAR PHARMACOLOGY, 2006, 70 (05) :1469-1480

[10]

Epigenetics and Metabolism [J].

Keating, Samuel T. ;

El-Osta, Assam .

CIRCULATION RESEARCH, 2015, 116 (04) :715-736

← 1 2 3 4 5 →