Wild type (WT) and Aconitate decarboxylase 1 knockout (Acod1-/-) BMDM treated with Imiquimod for 12h
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE250384 | GEO | 2024/04/17
REPOSITORIES: GEO
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Project description:Brucellosis is one of the most widespread bacterial zoonoses worldwide. Here, our aim was to identify the effector mechanisms controlling the early stages of intranasal infection with Brucella in C57BL/6 mice. During the first 48 hours of infection, alveolar macrophages (AMs) are the main cells infected in the lungs. Using RNA sequencing, we identified the aconitate decarboxylase 1 gene (Acod1; also known as Immune responsive gene 1), as one of the genes most upregulated in murine AMs in response to B. melitensis infection at 24 hours post-infection. Upregulation of Acod1 was confirmed by RT-qPCR in lungs infected with B. melitensis and B. abortus. We observed that Acod1-/- C57BL/6 mice display a higher bacterial load in their lungs than wild-type (wt) mice following B. melitensis or B. abortus infection, demonstrating that Acod1 participates in the control of pulmonary Brucella infection. The ACOD1 enzyme is mostly produced in mitochondria of macrophages, and converts cis-aconitate, a metabolite in the Krebs cycle, into itaconate. Dimethyl itaconate (DMI), a chemically-modified membrane permeable form of itaconate, has a dose-dependent inhibitory effect on Brucella growth in vitro. Interestingly, modelling studies suggest the binding of itaconate into the binding site of isocitrate lyase. DMI does not inhibit multiplication of the isocitrate lyase deletion mutant ∆aceA B. abortus in vitro. Finally, we observed that, unlike the wt strain, the ∆aceA B. abortus strain multiplies similarly in wt and Acod1-/- C57BL/6 mice. These data suggest that bacterial isocitrate lyase might be a target of itaconate in AMs.
2021-09-21 | GSE180699 | GEO
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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Project description:Itaconate has emerged as a critical immunoregulatory metabolite. Here, we examined the therapeutic potential of itaconate in atherosclerosis. We found that both itaconate and the enzyme that synthesizes it, aconitate decarboxylase 1 (Acod1, also known as “immune-responsive gene 1”/IRG1) are upregulated during atherogenesis in mice. Here we analzyed the anatomy of atherosclerotic plaques from wildtype and Acod1-/- mice through single cell RNA-seq.
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Project description:Lung metastasis is the principal cause of breast cancer-related mortality. Neutrophils have emerged as an important component of the tumor microenvironment (TME), supporting tumor proliferation and mediating immunosuppression. Here, we show that aconitate decarboxylase 1 (Acod1) is highly expressed in tumor-infiltrating neutrophils and promotes breast cancer lung metastasis by supporting neutrophil survival in the TME. Acod1 expression is regulated by tumor-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) through the JAK/STAT signaling pathway and CCAAT/enhancer-binding protein beta (C/EBPβ) transcription factor activity. Acod1 loss in tumor-infiltrating neutrophils leads to ferroptosis-like cell death, resulting in decreased frequency of neutrophils in the TME. Mechanistically, itaconate, the product of Acod1, activates nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in upregulated antioxidant responses and decreased lipid-reactive oxygen species. Genetical deletion of Acod1 in neutrophils suppresses lung metastasis of breast cancer in mouse models by decreasing neutrophil-lymphocyte ratio and elevating cytotoxic T cell response. Importantly, genetic targeting of Acod1 enhances the anti-tumor efficacy of immune checkpoint blockade. Overall, our findings reveal a mechanism of how immunosuppressive neutrophils survive in the harsh TME and support Acod1-targeting approaches for cancer treatment.
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Project description:RNA-sequencing demonstrated Acod1 (Aconitate decarboxylase 1) as one of the top genes induced by air polution particulate matter (PM) in macrophages. We therefore sought to determine the effect of both exogenous itaconate (4-octyl itaconate) and endogenous itaconate on PM-induced inflammation in macrophages through RNA sequencing.
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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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Project description:Borrelia burgdorferi (Bb), which causes Lyme disease, establishes long term infection and leads to disease manifestations that are mostly a result of host immune responses to the pathogen. Disease symptoms often resolve without treatment, suggesting innate immune memory may play a role in dampening inflammation over time. We used an in vitro model of repeated stimulations in macrophage and performed RNA sequencing on acute and memory states. We categorized differentially expressed genes based on their response to acute infection as well as their memory response compared to acute. We discuss four expression subsets representing important cellular changes to repeated stimulation and focus on genes that are negative regulators of inflammation induced during the acute phase and mediate long-term immunosuppression. We identified Aconitate decarboxylase 1 (Acod1), a negative regulator of inflammatory responses, and confirmed its role during in vivo long-term infection with Bb, with a specific role in Lyme carditis.
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Project description:The goal of the study is to examine changes in tumor gene expression after imiquimod treatment. RNA was extracted from spontaneous tumors in control mice (n=4) and in imiquimod-treated mice (n=4). Gene expression was compared between the control group and the treated group. In the imiquimod treatment group, the mice received topical treatment of 5% imiquimod cream (Aldara) on shaved skin at the site of spontaneous tumors for one treatment cycle (3 consecutive days). RNA was extracted from 4 spontaneous tumors from neu-tg mice treated with topical imiquimod for 1 cycle and 4 spontaneous tumors from control mice
2010-06-24 | E-GEOD-20032 | biostudies-arrayexpress
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.
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Project description:Imiquimod is a Toll-like receptor (TLR)-7 agonist capable of inducing complete clearance of basal cell carcinoma (BCC) and other cutaneous malignancies. We hypothesized that the characterization of the early transcriptional events induced by imiquimod may provide insights about immunological events preceding acute tissue and/or tumor rejection. We report a paired analysis of adjacent punch biopsies obtained pre- and post-treatment from 36 patients with BCC subjected to local application of imiquimod (N = 22) or vehicle cream (N=14) in a blinded, randomized protocol. Four treatments were assessed (q12 applications for 2 or 4 days, or q24 hrs for 4 or 8 days). RNA was amplified and hybridized to 17.5K cDNA arrays. All treatment schedules similarly affected the transcriptional profile of BCC; however, the q12 X 4days regimen, associated with highest effectiveness, induced the most changes with 637 genes unequivocally stimulated by imiquimod. A minority of transcripts (98 genes) confirmed previous reports of interferon-Â involvement. The remaining 539 genes portrayed additional immunological functions predominantly involving the activation of cellular innate and adaptive immune-effector mechanisms. Importantly, these effector signatures recapitulate previous observations of tissue rejection in the context of cancer immunotherapy, acute allograft rejection and autoimmunity. This study based on a powerful and reproducible model of cancer eradication by innate immune mechanisms provides the first insight in humans of the early transcriptional events associated with immune rejection. This model is likely representative of constant immunological pathways through which innate and adaptive immune responses combine to induce tissue destruction. Keywords: compound treatment design We report a paired analysis of adjacent punch biopsies obtained pre- and post-treatment from 36 patients with BCC subjected to local application of imiquimod (N = 22) or vehicle cream (N=14) in a blinded, randomized protocol. Four treatments were assessed (q12 applications for 2 or 4 days, or q24 hrs for 4 or 8 days). RNA was amplified and hybridized to 17.5K cDNA arrays.
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