Oncometabolite d -2HG alters T cell metabolism to impair CD8 ⁺ T cell function

Science, Journal Year: 2022, Volume and Issue: 377(6614), P. 1519 - 1529

Published: Sept. 29, 2022

Gain-of-function mutations in isocitrate dehydrogenase (IDH) human cancers result the production of d-2-hydroxyglutarate (d-2HG), an oncometabolite that promotes tumorigenesis through epigenetic alterations. The cancer cell-intrinsic effects d-2HG are well understood, but its tumor cell-nonautonomous roles remain poorly explored. We compared with enantiomer, l-2HG, and found tumor-derived was taken up by CD8+ T cells altered their metabolism antitumor functions acute reversible fashion. identified glycolytic enzyme lactate (LDH) as a molecular target d-2HG. inhibition LDH drive metabolic program immune cell signature marked decreased cytotoxicity impaired interferon-γ signaling recapitulated clinical samples from patients IDH1 mutant gliomas.

Language: Английский

---

Intracellular and Intercellular Aspects of Macrophage Immunometabolism in Atherosclerosis

Circulation Research, Journal Year: 2020, Volume and Issue: 126(9), P. 1209 - 1227

Published: April 23, 2020

Macrophage immunometabolism, the changes in intracellular metabolic pathways that alter function of these highly plastic cells, has been subject intense interest past few years, part because macrophage immunometabolism plays important roles atherosclerosis and other inflammatory diseases. In this review article, Compendium on Atherosclerosis , we introduce concepts (1) immunometabolism—the canonical intrinsic cell activation leading to metabolism, which turn cellular function; (2) intercellular immunometabolism—conditions intermediates metabolism are transferred from one another, thereby altering recipient cell. The recent discovery metabolite cargo dead dying cells ingested through efferocytosis by macrophages can downstream efferocyte is markedly changing way think about immunometabolism. Metabolic transitions contribute their functions all stages atherosclerosis, lesion initiation formation advanced lesions characterized necrotic cores, regression following aggressive lipid lowering. This article discusses advances our understanding different aspects atherosclerosis. With increasing new exciting potential targets for intervention emerging.

Language: Английский

---

D-mannose suppresses macrophage IL-1β production

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Dec. 11, 2020

Abstract D-mannose is a monosaccharide approximately hundred times less abundant than glucose in human blood. Previous studies demonstrated that supraphysiological levels of inhibit tumour growth and stimulate regulatory T cell differentiation. It not known whether metabolism affects the function non-proliferative cells, such as inflammatory macrophages. Here, we show suppresses LPS-induced macrophage activation by impairing IL-1β production. In vivo, mannose administration improves survival mouse model endotoxemia well decreases progression DSS-induced colitis. Phosphomannose isomerase controls response LPS-activated macrophages to D-mannose, which impairs raising intracellular mannose-6-phosphate levels. Such alterations result suppression succinate-mediated HIF-1α activation, imposing consequent reduction Il1b expression. Disclosing an unrecognized metabolic hijack our study points towards safe utilization effective intervention against conditions.

Language: Английский

---

Immune‐Responsive Gene 1/Itaconate Activates Nuclear Factor Erythroid 2–Related Factor 2 in Hepatocytes to Protect Against Liver Ischemia–Reperfusion Injury

Hepatology, Journal Year: 2020, Volume and Issue: 72(4), P. 1394 - 1411

Published: Jan. 30, 2020

Background and Aims Itaconate, a metabolite of the tricarboxylic acid cycle, plays anti‐inflammatory roles in macrophages during endotoxemia. The mechanisms underlying its have been shown to be mediated by modulation oxidative stress, an important mechanism hepatic ischemia–reperfusion (I/R) injury. However, role itaconate liver I/R injury is unknown. Approach Results We found that deletion immune‐responsive gene 1 (IRG1), encoding for enzyme producing itaconate, exacerbated systemic inflammation. Furthermore, bone marrow adoptive transfer experiments indicated IRG1 both hematopoietic nonhematopoietic compartments contributes protection after I/R. Interestingly, expression was up‐regulated hepatocytes hypoxia/reoxygenation‐induced stress. Modulation levels regulated hepatocyte cell death. Importantly, addition 4‐octyl significantly improved death our data nuclear factor erythroid 2–related 2 (Nrf2) required protective effect on mouse human against stress–induced Our studies document acute setting sterile induced Specifically, we provide evidence IRG1/itaconate pathway activates Nrf2‐mediated antioxidative response protect from Conclusions expand importance nonimmune cells identify as potential therapeutic strategy this unfavorable postsurgical complication.

Language: Английский

---

Cytokine-like Roles for Metabolites in Immunity

Molecular Cell, Journal Year: 2020, Volume and Issue: 78(5), P. 814 - 823

Published: April 24, 2020

Language: Английский

---

Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses

Life, Journal Year: 2021, Volume and Issue: 11(1), P. 69 - 69

Published: Jan. 19, 2021

The tricarboxylic acid cycle (TCA) is a series of chemical reactions used in aerobic organisms to generate energy via the oxidation acetylcoenzyme A (CoA) derived from carbohydrates, fatty acids and proteins. In eukaryotic system, TCA occurs completely mitochondria, while intermediates are retained inside mitochondria due their polarity hydrophilicity. Under cell stress conditions, can become disrupted release contents, which act as danger signals cytosol. Of note, may also leak dysfunctioning regulate cellular processes. Increasing evidence shows that metabolites substantially involved regulation immune responses. this review, we aimed provide comprehensive systematic overview molecular mechanisms each intermediate play key roles regulating immunity discuss its implication for activation suppression.

Language: Английский

---

Crosstalk between glucose metabolism, lactate production and immune response modulation

Cytokine & Growth Factor Reviews, Journal Year: 2022, Volume and Issue: 68, P. 81 - 92

Published: Nov. 7, 2022

Language: Английский

---

Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses

Nature Cell Biology, Journal Year: 2022, Volume and Issue: 24(3), P. 353 - 363

Published: March 1, 2022

Language: Английский

---

Targeting memory T cell metabolism to improve immunity

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(1)

Published: Jan. 3, 2022

Vaccination affords protection from disease by activating pathogen-specific immune cells and facilitating the development of persistent immunologic memory toward vaccine-specific pathogen. Current vaccine regimens are often based on efficiency acute response, not necessarily generation cells, in part because mechanisms underlying efficient remain incompletely understood. This Review describes recent advances defining T cell metabolism how these might be altered patients affected mitochondrial diseases or metabolic syndrome, who show higher susceptibility to recurrent infections rates failure. It discusses this new understanding could add way we think about memory, development, cancer immunotherapy.

Language: Английский

---

Methionine deficiency facilitates antitumour immunity by altering m⁶A methylation of immune checkpoint transcripts

Gut, Journal Year: 2022, Volume and Issue: 72(3), P. 501 - 511

Published: July 8, 2022

Objective Methionine metabolism is involved in a myriad of cellular functions, including methylation reactions and redox maintenance. Nevertheless, it remains unclear whether methionine metabolism, RNA antitumour immunity are molecularly intertwined. Design The effect methionine-restricted diet (MRD) feeding was assessed murine models. mechanisms YTH domain-containing family protein 1 (YTHDF1) tumour immune escape were determined vitro vivo. synergistic effects MRD or YTHDF1 depletion with PD-1 blockade also investigated. Results We found that dietary restriction reduced growth enhanced by increasing the number cytotoxicity tumour-infiltrating CD8 + T cells different mouse Mechanistically, S-adenosylmethionine derived from promoted N 6 -methyladenosine (m A) translation checkpoints, PD-L1 V-domain Ig suppressor cell activation (VISTA), cells. Furthermore, m A-specific binding inhibited restoring infiltration cells, synergised for better control. Clinically, expression correlated poor prognosis immunotherapy outcomes cancer patients. Conclusions play critical role anticancer through regulating functions Targeting could be potential new strategy immunotherapy.

Language: Английский

---