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Immune-Responsive Gene 1 expression in myeloid cells prevents neutrophil mediated immunopathology during Mycobacterium tuberculosis infection [macrophage]

ABSTRACT: Immune-Responsive Gene 1 (Irg1) is a mitochondrial enzyme that produces itaconate under inflammatory conditions principally in cells of myeloid lineage. Cell culture studies suggest that itaconate regulates inflammation through inhibitory effects on cytokine and reactive oxygen species production. To evaluate the functions of Irg1 in vivo, we challenged wild-type (WT) and Irg1-/- mice with Mycobacterium tuberculosis (Mtb) and monitored disease progression. Irg1-/- but not WT mice succumbed rapidly to Mtb, and mortality was associated with increased infection, inflammation, and pathology. Infection of LysM-Cre Irg1fl/fl, MPR8-Cre Irg1fl/fl, and CD11c-Cre Irg1fl/fl conditional knockout mice along with neutrophil depletion experiments revealed a role for Irg1 in alveolar macrophages and LysM+ myeloid cells in preventing neutrophil-mediated immunopathology and disease. RNA-seq analyses suggest that Irg1 and its production of itaconate temper Mtb-induced inflammatory responses in myeloid cells at the transcriptional level. Thus, Irg1 modulates inflammation to curtail Mtb-induced lung disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE108188 | GEO | 2018/02/15

REPOSITORIES: GEO

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Immune-Responsive Gene 1 expression in myeloid cells prevents neutrophil mediated immunopathology during Mycobacterium tuberculosis infection, in vivo neutrophil data

Project description:Immune-Responsive Gene 1 (Irg1) is a mitochondrial enzyme that produces itaconate under inflammatory conditions principally in cells of myeloid lineage. Cell culture studies suggest that itaconate regulates inflammation through inhibitory effects on cytokine and reactive oxygen species production. To evaluate the functions of Irg1 in vivo, we challenged wild-type (WT) and Irg1 KO mice with Mycobacterium tuberculosis (Mtb) and monitored disease progression. Irg1 KO but not WT mice succumbed rapidly to Mtb, and mortality was associated with increased infection, inflammation, and pathology. Infection of LysM-Cre Irg1 flox, MPR8-Cre Irg1 flox, and CD11c-Cre Irg1 flox conditional knockout mice along with neutrophil depletion experiments revealed a role for Irg1 in alveolar macrophages and LysM+ myeloid cells in preventing neutrophil-mediated immunopathology and disease. RNA-seq analyses suggest that Irg1 and its production of itaconate temper Mtb-induced inflammatory responses in myeloid cells at the transcriptional level. Thus, Irg1 modulates inflammation to curtail Mtb-induced lung disease.

2017-08-30 | GSE98457 | GEO

Immune-Responsive Gene 1 expression in myeloid cells prevents neutrophil mediated immunopathology during Mycobacterium tuberculosis infection, in vitro neutrophils data

2017-08-30 | GSE98456 | GEO

Staphylococcus aureus stimulates neutrophil itaconate production that suppresses the oxidative burst

Project description:Neutrophils are critical in the host defense against Staphylococcus aureus, a major human pathogen. However, even in the setting of a robust neutrophil response, S. aureus can cause persistent infection. Here we demonstrate that S. aureus impairs neutrophil function by triggering the production of the anti-inflammatory metabolite, itaconate. The enzyme that synthesizes itaconate, Irg1, is selectively expressed in neutrophils during S. aureus pneumonia. Itaconate inhibits neutrophil glycolysis and oxidative burst, which impairs survival and bacterial killing. In a murine pneumonia model, neutrophil Irg1 expression protects critical lung cell populations from oxidative stress but compromises bacterial clearance. S. aureus is thus able to evade innate immune clearance by targeting neutrophil metabolism and inducing the production of the antiinflammatory metabolite itaconate.

2023-01-01 | GSE215195 | GEO

Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation

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.

2024-01-29 | PXD047706 | Pride

Effects of itaconate on gene expression in mouse CD8 T cells

Project description:The tumor microenvironment possesses multiple overlapping mechanisms that suppress anti-tumor immunity. Itaconate is a metabolite produced from the Krebs cycle intermediate cis-aconitate by the activity of immune-responsive gene 1 (IRG1). While it is known to be immune modulatory, the role of itaconate in anti-tumor immunity is unclear. Here, we demonstrate that myeloid-derived suppressor cells (MDSCs) secreted itaconate that can be taken up by CD8+ T cells and suppress their proliferation, cytokine production, and cytolytic activity. Metabolite profiling, stable-isotope tracing and metabolite supplementation studies indicated that itaconate suppressed biosynthesis of aspartate and serine/glycine in CD8+ T cells to attenuate their proliferation. Moreover, stromal deletion of IRG1 in mice bearing allografted tumors resulted in decreased tumor growth, inhibited the immune suppressive activities of MDSCs, reduced levels of itaconate in tumors, promoted anti-tumor immunity of CD8+ T cells, and enhanced the anti-tumor activity of anti-PD-1 antibody treatment. Importantly, we found a significant negative correlation between IRG1 expression and response to PD-1 immune checkpoint blockade in melanoma patients. Our findings not only reveal a previously unknown role of itaconate as an immune checkpoint metabolite secreted from MDSCs to suppress CD8+ T cells, but also establish IRG1 as a novel myeloid-selective target in immunometabolism to promote anti-tumor immunity and enhance the efficacy of immune checkpoint protein blockade.

2022-11-15 | GSE190028 | GEO

IMMUNE-RESPONSIVE GENE 1 REGULATES ATHEROSCLEROTIC PLAQUE INFLAMMATION III

Project description:Atherosclerosis is the major underlying cause of cardiovascular disease (CVD) mortality and is fueled by a failure to resolve inflammation within the vessel wall1. The mechanisms underpinning sustained inflammation within this microenvironment are not fully elucidated. A more comprehensive understanding of the immunoregulatory pathways modulating inflammation in this context holds the potential to inform the development of more specific therapies. Immune responsive gene 1 (Irg1) is an enzyme that diverts cis-aconitate from the TCA cycle and produces the metabolite itaconate, which elicits immunological tolerance in the context of microbial infection2–4. We hypothesized that the IRG1-itaconate axis restricts inflammation in the atherosclerotic plaque.

2024-03-19 | GSE253555 | GEO

IMMUNE-RESPONSIVE GENE 1 REGULATES ATHEROSCLEROTIC PLAQUE INFLAMMATION II

2024-03-19 | GSE252242 | GEO

IMMUNE-RESPONSIVE GENE 1 REGULATES ATHEROSCLEROTIC PLAQUE INFLAMMATION I

2024-03-19 | GSE252241 | GEO

Whole-transcriptome analysis of spleens from WT and myeloid ferritin H-deficient animals upon Salmonella infection

Project description:Iron is an essential nutrient for humans as well as for pathogens. Hence, its correct distribution at the systemic and cellular level is mandatory for mounting an effective innate immune defense. Here we delved into the role of macrophage-expressed iron storing protein ferritin H (FTH) in immune response against the model intracellular pathogen Salmonella Typhimurium. Mice lacking FTH in the myeloid lineage (LysM-Cre+/+ Fthfl/fl) displayed impaired iron storage capacities in tissue leukocyte compartment, increased levels of labile iron in macrophages and an accelerated macrophage-mediated iron turnover. Without iron supplementation, wildtype (WT) and LysM-Cre+/+ Fthfl/fl animals showed comparable susceptibility to Salmonella infection. Interestingly, iron supplementation rapidly elicited symptoms of cytokine storm and drastically shortened survival of LysM-Cre+/+ Fthfl/fl mice. Mechanistically, we traced this phenotype back to labile iron-mediated hyperactivity of the inflammasome in FTH-deficient macrophages, culminating in excessive IL-1β secretion and secondary triggering of NF-kappaB-dependent inflammatory circuits. Accordingly, bacterial burden and cytokine levels in iron-loaded LysM-Cre+/+ Fthfl/fl mice could be effectively kept at bay by pharmacological inflammasome and IL-1β blockade. These findings point towards a previously unrecognized role of ferritin as an inhibitor of iron-dependent inflammasome activity in macrophages and a checkpoint of systemic innate response.

2021-02-12 | GSE145114 | GEO

NAD(H) homeostasis is essential for host protection mediated by glycolytic myeloid cells in tuberculosis

Project description:To investigate the role of LDHA in myeloid cells in the response to pulmonary infection with Mycobacterium tuberculosis, we infected LDHAfl/fl:LysM+/- mice with Mtb-H37Rv via the aerosol route. We then performed gene expression profiling analysis using data obtained from RNA-seq of the lungs of these animals at 4 and 30 weeks post infection.

2023-08-09 | GSE234115 | GEO

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