Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity
By R. Arts, B. Novaković, R. ter Horst, A. Carvalho, S. Bekkering, E. Lachmandas, F. Rodrigues, Ricardo Silvestre, Shih-Chin Cheng, Shuang-Yin Wang and 19 more. Cell Metabolism, 2016
765 citations recorded by the source corpus.
SUMMARY 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.
Subfields: Genetics, Immunology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/ca158a656323f8caf6fba82576722e075fa68722
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Citations in the corpus
- Immunosenescence: molecular mechanisms and diseases (2023, background): “Because tricarboxylic acid cycle intermediates such as fumarate, succinate, and α-ketoglutarate have been identified as vital epigenetic regulators, studies targeting mitochondria and their metabolites are considered critical to integrate metabolism with epigenetic modifications.(212) Apart from bio”
- Metabolic Induction of Trained Immunity through the Mevalonate Pathway. (2018, neutral): “Previously, we have shown an increase in intracellular citrate in b-glucan-trained cells, which might provide evidence of a similar mechanism inmonocytes (Arts et al., 2016b).”
- Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity (2018, methodology): “Pathogen-associated molecular patterns or cytokines induce a complex immunometabolic program in monocytes and macrophages, enabling a robust cellular response to re-stimulation, especially with regard to cytokine production (Arts et al., 2016a; Netea et al., 2016; Quintin et al., 2012).”