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ACOD1 regulates microglial arginine metabolism and inflammatory responses

ABSTRACT: ACOD1 regulates microglial arginine metabolism and inflammatory responses

PROVIDER: PRJNA1275887 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR33953100_1.fastq.gz	Fastqsanger.gz
	SRR33953100_2.fastq.gz	Fastqsanger.gz
	SRR33953101_1.fastq.gz	Fastqsanger.gz
	SRR33953101_2.fastq.gz	Fastqsanger.gz
	SRR33953102_1.fastq.gz	Fastqsanger.gz

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ACOD1 regulates microglial arginine metabolism and inflammatory responses

Project description:Itaconate is produced by inflammatory macrophages and negatively feedbacks on inflammation. It is synthesized by aconitate decarboxylase 1 (ACOD1) from cis-aconitate, a metabolite of the tricarboxylic acid cycle. Here, we studied the role of ACOD1 in the inflammatory response of microglia, the resident macrophage-like cells of the brain. Similarly to macrophages, ACOD1 deficient microglia displayed a stronger inflammatory response to lipopolysaccharide (LPS) compared to their wild type counterparts. ACOD1 deficiency reprogramed arginine metabolism by enhancing argininosuccinate synthesis in the expense of polyamine synthesis in an ACLY-dependent manner. These findings provide new insights in the immunometabolic role of ACOD1 in inflammatory microglia.

2025-06-15 | GSE299665 | GEO

Acod1-mediated effect on osteoclast differentiation

Project description:Enhanced osteoclast-mediated bone erosion is a prominent hallmark of rheumatoid arthritis. Emerging evidence suggests that this process is facilitated by metabolic dysregulation of osteoclasts. The mitochondrial enzyme aconitate decarboxylase 1 (Acod1, also known as immune responsive gene 1 [Irg1]) serves as a mediator between the metabolic condition and the functional state of different types of cells. Acod1-deficient mice are characterized by enhanced osteoclast differentiation and bone erosion in an inflammatory arthritis model, while therapeutic treatment with the itaconate-derivative 4-octyl-itaconate (4-OI) alleviates the disease phenotype in experimental arthritis. To ascertain the influence of the Acod1-itaconate axis on the genomic transcriptional network of osteoclasts, we performed a whole transcriptome RNA sequencing analysis with fully differentiated osteoclasts from WT and Acod1-deficient mice that were cultured in the presence or absence of 4-OI.

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Effects of Acod1 loss on liver responses to fat overnutrition

Project description:ACOD1 is the enzyme repurposing cisaconitate from the tricarboxylic acid (TCA) cycle in the mitochondria to produce itaconate, a metabolite with anti-inflammatory and tolerogenic functions. In particular, itaconate accumulation in macrophages is known to oppose pro-inflammatory cytokine production mainly by inhibiting succinate dehydrogenase activity, activating the NRF2 and ATF3driven responses and inhibiting NLRP3. Itaconate biosynthesis was found to be induced in the liver of mice exposed to ischemia reperfusion (I/R) stress and to oppose the resulting tissue injury by sustaining hepatoprotective antioxidant programs. Whether ACOD1 plays a role in the homeostatic response of liver to different noninfectious injuring conditions remains largely unexplored. This study investigates the contribution of itaconate biosynthesis in the response of liver to dietary lipid overload and in the development of associated nonalcoholic fatty liver disease.

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Transcriptomic signature of white adipose tissue from wild type and Acod1-deficient mice in response to high fat diet

Project description:Aconitate decarboxylase 1 (ACOD1) is the enzyme synthesizing itaconate, an immuno-regulatory metabolite tuning host-pathogen interactions. Such functions are achieved by affecting metabolic pathways regulating inflammation and microbe survival. However, at the whole-body level, metabolic roles of itaconate remain largely unresolved. By using multiomics-integrated approaches, here we show that ACOD1 responds to high-fat diet consumption in mice by promoting gut microbiota alterations supporting metabolic disease. Genetic disruption of itaconate biosynthesis protects mice against obesity, alterations in glucose homeostasis and liver metabolic dysfunctions by decreasing meta-inflammatory responses to dietary lipid overload. Mechanistically, fecal metagenomics and microbiota transplantation experiments demonstrate such effects are dependent on an amelioration of the intestinal ecosystem composition, skewed by high-fat diet feeding towards obesogenic phenotype. In particular, unbiased fecal microbiota profiling and axenic culture experiments point towards a primary role for itaconate in inhibiting growth of Bacteroidaceae and Bacteroides, family and genus of Bacteroidetes phylum, the major gut microbial taxon associated with metabolic health. Specularly to the effects imposed by Acod1 deficiency on fecal microbiota, oral itaconate consumption enhances diet-induced gut dysbiosis and associated obesogenic responses in mice. Unveiling an unrecognized role of itaconate, either endogenously produced or exogenously administered, in supporting microbiota alterations underlying diet-induced obesity in mice, our study points ACOD1 as a target against inflammatory consequences of overnutrition.

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Acod1-mediated effect on osteoclast differentiation

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Phosphoproteomics identifies microglial Siglec-F inflammatory response during neurodegeneration

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TPL2 kinase activity regulates microglial inflammatory responses and promotes neurodegeneration in tauopathy mice

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