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ABCG2 is an itaconate exporter that limits TFEB-mediated lysosomal biogenesis to impair antibacterial innate immunity

ABSTRACT: Itaconate is a metabolite that synthesized from cis-aconitate in mitochondria and transported into cytosol to exert multiple regulatory effects in macrophages. However, the mechanism by which itaconate exits from the cytosol of activated macrophages remains unknown. Using a genetic screen, we reveal that cytosolic itaconate is exported by ABCG2, an ATP-binding cassette (ABC) transporter, in an ATPase-dependent manner in human and mouse macrophages.

ORGANISM(S): Homo sapiens

PROVIDER: GSE225712 | GEO | 2024/05/01

REPOSITORIES: GEO

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Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response

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Project description:One primary metabolic manifestation of inflammation is the diversion of cis-aconitate within the tricarboxylic acid (TCA) cycle to synthesize the immunometabolite itaconate. Itaconate is well established to possess immunomodulatory and metabolic effects within myeloid cells and lymphocytes, however, its effects in other organ systems during sepsis remain less clear. Utilizing Irg1 knockout mice that are deficient in synthesizing itaconate, we aimed at understanding the metabolic role of itaconate in the liver and systemically during sepsis. We find itaconate aids in lipid metabolism during sepsis. Specifically, Irg1 KO mice develop a heightened level of hepatic steatosis when induced with polymicrobial sepsis. Proteomics analysis reveal enhanced expression of enzymes involved in fatty acid oxidation in following 4-ocytl itaconate (4-OI) treatment in vitro. Downstream analysis reveals itaconate stabilizes the expression of the mitochondrial fatty acid uptake enzyme CPT1a, mediated by its hypoubiquitination. Chemoproteomic analysis revealed itaconate interacts with proteins involved in protein ubiquitination as a potential mechanism underlying its stabilizing effect on CPT1a. From a systemic perspective, we find itaconate deficiency triggers a hypothermic response following endotoxin stimulation, potentially mediated by brown adipose tissue (BAT) dysfunction. Finally, by use of metabolic cage studies, we demonstrate Irg1 KO mice rely more heavily on carbohydrates versus fatty acid sources for systemic fuel utilization in response to endotoxin treatment. Our data reveal a novel metabolic role of itaconate in modulating fatty acid oxidation during polymicrobial sepsis.

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Project description:Itaconate is a metabolite naturally produced in large amounts in macrophages after exposure to immune stimulation. Following the discovery of itaconate’s immunoregulatory properties, several ester derivatives of this dicarboxylic acid were designed to further examine its role. We evaluated the metabolic, electrophilic, and immunologic profiles of macrophages treated with unmodified itaconate and a panel of itaconate derivatives. We found that only unmodified itaconate strongly enhances LPS-induced IFNb secretion after 12h pre-treatment. Thus, we compared the transcriptional profile of wild type and Irg1-/- cells, which are unable to produce itaconate, after 24h LPS stimulation. We find that cells lacking itaconate have impaired downstream type I interferon signaling, and that addition of itaconate Irg1-/- BMDMs restores this signaling back to levels comparable to wild type. This data highlights the role of itaconate as an immunoregulatory metabolite, and highlights the importance of using unmodified itaconate or genetic knockout models in future mechanistic studies.

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Project description:Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation mechanism accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the downstream pro-inflammatory IL-1β-HIF1a axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions via its effect on succinate dehydrogenase, by inhibiting conversion of succinate to fumarate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1-/- mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, changes in mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages.

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