Trained Immunity: Linking Obesity and Cardiovascular Disease across the Life-Course?
Bekkering, Siroon ; Saner, Christoph ; Riksen, Niels P. ; Netea, Mihai G. ; Sabin, Matthew A. ; Saffery, Richard ; Stienstra, Rinke ; Burgner, David P. - \ 2020
Trends in Endocrinology & Metabolism 31 (2020)5. - ISSN 1043-2760 - p. 378 - 389.
atherosclerosis - cardiovascular disease - inflammation - obesity - trained immunity
Obesity, a chronic inflammatory disease, is the most prevalent modifiable risk factor for cardiovascular disease. The mechanisms underlying inflammation in obesity are incompletely understood. Recent developments have challenged the dogma of immunological memory occurring exclusively in the adaptive immune system and show that the innate immune system has potential to be reprogrammed. This innate immune memory (trained immunity) is characterized by epigenetic and metabolic reprogramming of myeloid cells following endogenous or exogenous stimulation, resulting in enhanced inflammation to subsequent stimuli. Trained immunity phenotypes have now been reported for other immune and non-immune cells. Here, we provide a novel perspective on the putative role of trained immunity in mediating the adverse cardiovascular effects of obesity and highlight potential translational pathways.
Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity
Arts, Rob J.W. ; Novakovic, Boris ; Horst, Rob ter; Carvalho, Agostinho ; Bekkering, Siroon ; Lachmandas, Ekta ; Rodrigues, Fernando ; Silvestre, Ricardo ; Cheng, Shih Chin ; Wang, Shuang Yin ; Habibi, Ehsan ; Gonçalves, Luís G. ; Mesquita, Inês ; Cunha, Cristina ; Laarhoven, Arjan van; Veerdonk, Frank L. van de; Williams, David L. ; Meer, Jos W.M. van der; Logie, Colin ; O'Neill, Luke A. ; Dinarello, Charles A. ; Riksen, Niels P. ; Crevel, Reinout van; Clish, Clary ; Notebaart, Richard A. ; Joosten, Leo A.B. ; Stunnenberg, Hendrik G. ; Xavier, Ramnik J. ; Netea, Mihai G. - \ 2016
Cell Metabolism 24 (2016)6. - ISSN 1550-4131 - p. 807 - 819.
cholesterol metabolism - epigenetics - glutamine metabolism - glycolysis - trained immunity
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.