Type I interferon signaling and peroxisomal dysfunction contribute to enhanced inflammatory cytokine production in Irgm1-deficient macrophages
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PROVIDER: PRJNA1159166 | ENA |
REPOSITORIES: ENA
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Project description:The human IRGM gene has been linked to inflammatory diseases including sepsis and Crohn’s disease. Decreased expression of human IRGM, or of the mouse orthologues Irgm1 and Irgm2, leads to increased production of a number of inflammatory chemokines and cytokines in vivo and/or in cultured macrophages. Prior work has indicated that increased cytokine production is instigated by metabolic alterations and by changes in mitochondrial homeostasis; however, a comprehensive mechanism has not been elucidated. In the studies presented here, RNA deep sequencing and quantitative PCR were used to show that increases in cytokine production, as well as most changes in the transcriptional profile of Irgm1-/- bone marrow-derived macrophages (BMM), are dependent on increased type I IFN production seen in those cells. Metabolic alterations that drive increased cytokines in Irgm1-/- BMM - specifically increases in glycolysis and increased accumulation of acyl-carnitines - were unaffected by quenching type I IFN signaling. Dysregulation of peroxisomal homeostasis was identified as a novel upstream pathway that governs type I IFN production and inflammatory cytokine production. Collectively, these results enhance our understanding of the complex biochemical changes that are triggered by lack of Irgm1 and contribute to inflammatory disease seen with Irgm1-deficiency.
2024-12-26 | GSE276820 | GEO
Project description:The immunity-related GTPases (IRGs) are a family of proteins that are induced by interferon (IFN)-γ and play pivotal roles in immune and inflammatory responses. IRGs ostensibly function as dynamin-like proteins that bind to intracellular membranes and promote remodeling and trafficking of those membranes. Prior studies have shown that loss of Irgm1 in mice leads to increased lethality to bacterial infections as well as enhanced inflammation to non-infectious stimuli; however, the mechanisms underlying these phenotypes are unclear. In the studies reported here, we found that uninfected Irgm1-deficient mice displayed high levels of serum cytokines typifying profound autoinflammation. Similar increases in cytokine production were also seen in cultured, IFN-γ-primed macrophages that lacked Irgm1. A series of metabolic studies indicated that the enhanced cytokine production was associated with marked metabolic changes in the Irgm1-deficient macrophages, including increased glycolysis and an accumulation of long chain acylcarnitines. Cells were exposed to the glycolytic inhibitor, 2-deoxyglucose, or fatty acid synthase inhibitors to perturb the metabolic alterations, which resulted in dampening of the excessive cytokine production. These results suggest that Irgm1 deficiency drives metabolic dysfunction in macrophages in a manner that is cell-autonomous and independent of infectious triggers. This may be a significant contributor to excessive inflammation seen in Irgm1-deficient mice in different contexts.
| S-EPMC5377780 | biostudies-literature
Project description:To assess gene expression changes in Irgm1 (Lrg-47) deficient HSCs Keywords: genetic modification, knockout
2011-06-23 | GSE11591 | GEO
Project description:To assess gene expression changes in Irgm1 (Lrg-47) deficient HSCs Keywords: genetic modification, knockout A total of 6 samples were analyzed: 3 experimental replicates of Irgm1 HSCs were compared with 3 control replicates of WT HSCs
2011-06-22 | E-GEOD-11591 | biostudies-arrayexpress
Project description:Polymorphisms in the IRGM gene are associated with susceptibility to tuberculosis in humans. A murine ortholog of Irgm, Irgm1, is also essential for controlling Mycobacterium tuberculosis (Mtb) infection in mice. Multiple processes have been associated with IRGM1 activity that could impact the host response to Mtb infection, including roles in autophagy-mediated pathogen clearance and expansion of activated T cells. However, what IRGM1-mediated pathway is necessary to control Mtb infecion in vivo and the mechanistic basis for this control remains unknown. We dissected the contribution of IRGM1 to immune control of Mtb pathogenesis in vivo and found that Irgm1 deletion leads to higher levels of IRGM3-dependent type I interferon signaling. The increased type I interferon signaling precludes T cell expansion during Mtb infection. The absence of Mtb-specific T cell expansion in Irgm1 -/- mice results in uncontrolled Mtb infection in neutrophils and alveolar macrophages, which directly contributes to susceptibility to infection. Together, our studies reveal that IRGM1 is required to promote T cell-mediated control of Mtb infection in neutrophils, which is essential for the survival of Mtb-infected mice. These studies also uncover new ways type I interferon signaling can impact TH1 immune responses.
2024-07-31 | GSE271425 | GEO
Project description:We observed enhanced epithelial proliferation secondary to elevated Type I IFNs in multiple tissues of Irgm1-/- mice. We discovered that Type I IFNs signaled through macrophages to promote this epithelial hyperproliferation. To determine candidate factors that could play a role in this process, we performed whole genome microarray analysis of salivary gland, small intestine, and isolated colonic macrophages of Irgm1-/- mice and C57BL/6 WT controls. Genes enriched in at least 2 of the 3 sample sources were then screened for the ability to augment epithelial proliferation in vitro.
2015-01-03 | GSE59603 | GEO
Project description:We observed enhanced epithelial proliferation secondary to elevated Type I IFNs in multiple tissues of Irgm1-/- mice. We discovered that Type I IFNs signaled through macrophages to promote this epithelial hyperproliferation. To determine candidate factors that could play a role in this process, we performed whole genome microarray analysis of salivary gland, small intestine, and isolated colonic macrophages of Irgm1-/- mice and C57BL/6 WT controls. Genes enriched in at least 2 of the 3 sample sources were then screened for the ability to augment epithelial proliferation in vitro. RNA was extracted from three (small intestine and isolated colonic macrophage samples) or four (salivary gland samples) mice of each genotype (Irgm1-/- and WT). Both male and female six to nine week-old mice were used.
2015-01-03 | E-GEOD-59603 | biostudies-arrayexpress
Project description:Distinct retrograde signaling pathways have been identified for several cellular organelles. These pathways are important to maintain the function of these organelles in response to organelle-specific stress. Using Caenorhabditis elegans, we show for the first time that such a retrograde signaling also exists for peroxisomes. Analysis of the C. elegans transcriptome revealed that peroxisomal import stress caused by the knock-down of the peroxisomal matrix protein import receptor prx-5/PEX5 induces the compensatory up-regulation of genes involved in defense response and lipid metabolic processes, especially peroxisomal beta oxidation. We, therefore, propose that the peroxisomal retrograde signaling participates in the maintenance of peroxisomal function in response to peroxisomal import stress.
2020-12-19 | GSE156318 | GEO
Project description:Patients lacking multifunctional protein 2, the central enzyme of the peroxisomal β-oxidation pathway, develop retinopathy. This metabolic pathway is involved in the metabolism of very long chain (VLCFAs) and polyunsaturated (PUFAs) fatty acids, which are enriched in the photoreceptor outer segments (POS). The molecular mechanisms underlying the retinopathy remain however elusive. Here, we report that Mfp2-/- mice display decreased retinal function already at the age of 3 weeks, which is accompanied by a profound shortening of the photoreceptor outer and inner segments, but with preserved photoreceptor ultrastructure. Furthermore, Mfp2-/- retinas exhibit severe changes in gene expression with downregulation of genes involved in the phototransduction pathway and upregulation of inflammation related genes. Lipid profiling of the retina of Mpf2-/- mice revealed a profound reduction of DHA-containing phospholipids. This was likely due to a hampered systemic supply and retinal traffic of this PUFA, although we cannot exclude that the local defect of peroxisomal β-oxidation contributes to this DHA decrease. Moreover, VLC-PUFAs were also reduced, except those containing ≥34 carbons that accumulated. The latter suggests that there is an uncontrollable elongation of retinal PUFAs. In conclusion, we showed that intact peroxisomal β-oxidation is indispensable for retinal integrity, most likely by maintaining PUFA homeostasis.
2021-01-31 | GSE163770 | GEO
Project description:To understand the molecular mechanism by which Irgm1 controls innate immune homoestasis
2020-09-01 | E-MTAB-9164 | biostudies-arrayexpress