<i>Irg1</i> expression in myeloid cells prevents immunopathology during <i>M. tuberculosis</i> infection

Nair, Sharmila; Huynh, Jeremy P.; Lampropoulou, Vicky; Loginicheva, Ekaterina; Esaulova, Ekaterina; Gounder, Anshu P.; Boon, Adrianus C. M.; Schwarzkopf, Elizabeth A.; Bradstreet, Tara R.; Edelson, Brian T.; Artyomov, Maxim N.; Stallings, Christina L.; Diamond, Michael S.

doi:10.1084/jem.20180118

Cited by 222 publications

(256 citation statements)

References 21 publications

(39 reference statements)

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“…23 Their results demonstrated that the lungs from Irg1 À/À mice had increased percentages of infiltrated PMNs, indicating that Irg1 and its product itaconate function to limit inflammation by diminishing the accumulation of PMNs during M. tuberculosis infection. 23 Therefore, we hypothesized that the anti-inflammatory effects of DI treatment correlate with PMN infiltration. In this regard, our results show that treatment with DI effectively reduced MPO activity as well as PMN infiltration in infected corneas.…”

Section: Discussionmentioning

confidence: 98%

“…tested the effect of Irg1 on the accumulation of PMNs in the lungs during M. tuberculosis infection . Their results demonstrated that the lungs from Irg1 −/− mice had increased percentages of infiltrated PMNs, indicating that Irg1 and its product itaconate function to limit inflammation by diminishing the accumulation of PMNs during M. tuberculosis infection . Therefore, we hypothesized that the anti‐inflammatory effects of DI treatment correlate with PMN infiltration.…”

Section: Discussionmentioning

confidence: 99%

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Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO‐1 signaling pathway

Lin

Wang

et al. 2020

Immunol Cell Biol

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Dimethyl itaconate (DI) is a membrane‐permeable itaconate derivative with anti‐inflammatory functions. However, the anti‐inflammatory effect of DI has never been studied in fungal keratitis. In this study, we tested the protective effect of DI against fungal keratitis and assessed the role of NF‐E2‐related factor‐2 (Nrf2)/heme oxygenase‐1 (HO‐1) signaling in this process. Eyes of C57BL/6 (B6) mice were treated with 2 mm DI after infection with Aspergillus fumigatus. Human corneal epithelial cells (HCECs) were pretreated with 0.25 mm DI and then incubated with A. fumigatus. Clinical scoring, slit‐lamp photography, myeloperoxidase determination, flow cytometry and immunostaining were used to assess the disease response and treatment efficacy. PCR, Western blot and ELISA were used to assess the expression of interleukin‐1β (IL‐1β), chemokine (C–X–C motif) ligand 1, IL‐6, IL‐8, Nrf2 and HO‐1. In addition, quantification of viable fungi, absorbance assays and fluorimetry were used to measure DI fungistatic activity. We observed that DI‐treated eyes showed decreased clinical scores, fungal loads, polymorphonuclear neutrophil (PMN) infiltration and cytokine expression, compared with phosphate‐buffered saline‐treated infected eyes. DI treatment decreased the cytokine levels in infected corneas and in HCECs stimulated with A. fumigatus. Moreover, DI treatment increased Nrf2 and HO‐1 expression in corneas and nuclear Nrf2 accumulation in HCECs. DI‐induced cytokine downregulation was inhibited by pretreatment with an Nrf2 or HO‐1 inhibitor. Finally, DI treatment reduced the A. fumigatus absorbance and fungal mass. These data indicate that DI protects against fungal keratitis by limiting inflammation via the Nrf2/HO‐1 signaling pathway and that DI inhibits the growth of A. fumigatus.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO‐1 signaling pathway

Lin

Wang

et al. 2020

Immunol Cell Biol

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“…The overexpression of IRG1 also significantly inhibits LPS‐triggered production of TNF‐α, interleukin (IL)‐6 and interferon‐β in mouse macrophages . In contrast, knockout of IRG1 aggravates the inflammatory response in mouse bone marrow‐derived macrophages (BMDMs) challenged with LPS and myeloid cells infected with Mycobacterium tuberculosis . Furthermore, polymorphisms in the IRG1 gene are associated with the immune response to hepatitis B vaccination in the Chinese Han population …”

Section: Physiological Roles and Regulation Of Irg1mentioning

confidence: 99%

“…20 In contrast, knockout of IRG1 aggravates the inflammatory response in mouse bone marrow-derived macrophages (BMDMs) challenged with LPS 21 and myeloid cells infected with Mycobacterium tuberculosis. 22 Furthermore, polymorphisms in the IRG1 gene are associated with the immune response to hepatitis B vaccination in the Chinese Han population. 23 It has been reported that IRG1 is highly expressed in mouse macrophages in response to treatment with Tolllike receptor agonists 24 or infection with M. tuberculosis 25 or Chlamydia pneumoniae.…”

Section: Physiological Roles and Regulation Of Irg1mentioning

confidence: 99%

Itaconate: an emerging determinant of inflammation in activated macrophages

Zhang

Zheng

et al. 2018

Immunol Cell Biol

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Macrophages play a central role in innate immunity as the first line of defense against pathogen infection. Upon exposure to inflammatory stimuli, macrophages rapidly respond and subsequently undergo metabolic reprogramming to substantially produce cellular metabolites such as itaconate. As a derivate of the tricarboxylic acid cycle, itaconate is derived from the decarboxylation of cis‐aconitate mediated by immunoresponsive gene 1 in the mitochondrial matrix. It is well known that itaconate has a direct antimicrobial effect by inhibiting isocitrate lyase. Strikingly, two recent studies published in Nature showed that itaconate markedly decreases the production of proinflammatory mediators in lipopolysaccharide‐treated macrophages and ameliorates sepsis and psoriasis in animal models, revealing a novel biological action of itaconate beyond its regular roles in antimicrobial defense. The mechanism for this anti‐inflammatory effect has been proposed to involve the inhibition of succinate dehydrogenase, blockade of IκBζ translation and activation of Nrf2. These intriguing discoveries provide a new explanation for how macrophages are switched from a pro‐ to an anti‐inflammatory state to limit the damage and facilitate tissue repair under proinflammatory conditions. Thus, the emerging effect of itaconate as a crucial determinant of macrophage inflammation has important implications in further understanding cellular immunometabolism and developing future therapeutics for the treatment of inflammatory diseases. In this review, we focus on the roles of itaconate in controlling the inflammatory response during macrophage activation, providing a rationale for future investigation and therapeutic intervention.

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“…In turn, those activities are able to influence hostpathogen interactions, as it was shown in macrophages during Legionella pneumophila infection (Naujoks et al 2016;Price et al 2019). More recently, Nair et al showed that IRG1-deficient mice are highly susceptible to Mtb infection, while no aberrant phenotypes were found during influenza A virus or Listeria monocytogenes infection (Nair et al 2018). Their findings suggest that IRG1 expression in myeloid cells shape immunometabolic host responses by regulating neutrophil-dependent inflammation during Mtb infection of the lung.…”

Section: Introductionmentioning

confidence: 98%

IRG1 controls host responses to restrict Mycobacterium tuberculosis infection

Hoffmann

Machelart

Belhaouane

et al. 2019

Preprint

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Mycobacterium tuberculosis (Mtb), the pathogen causing human tuberculosis, has evolved multiple strategies to successfully prevent clearance by immune cells and to establish dissemination and long-term survival in the host. The modulation of host immunity to maximize pathogen elimination while minimizing inflammation-mediated tissue damage may provide another tool to fight drug-resistant Mtb strains.Metabolic reprogramming of immune cell populations can dramatically influence the outcome of immune responses and modulate antimicrobial properties of infected host cells, nicely demonstrating that metabolites are tightly linked to immune cell effector functions. One important endogenous metabolite of the Krebs cycle is itaconate, which has potent bactericidal activity by inhibiting isocitrate lyase and the glyoxylate shunt within prokaryotes including mycobacteria. Recent findings show that itaconate and the catalytic enzyme responsible for its generation in mammalian cells, i.e. IRG1 (immune-responsive gene 1), also modify inflammatory signaling of infected cells enhancing host defense pathways.Here, we demonstrate that IRG1 is recruited to Mtb-containing phagosomes and that it influences the host response controlling Mtb infection. While IRG1 deficiency does not affect uptake of Mtb by macrophages and dendritic cells (DCs) in vitro, it increases the intracellular replication of Mtb. Concomitantly, in comparison to wild type cells, IRG1-deficient macrophages and DCs have increased levels of lipid droplets, a correlate of inflammation. These intracellular organelles store triacylglycerol and phospholipids that are hijacked by Mtb as reservoir of host nutrients. Exposure of IRG1-deficient mice to M. bovis BCG via the intranasal route induced neither lethality nor severe lung immunopathology, while IRG1-deficient mice were highly susceptible to Mtb infection resulting in animal death three weeks post-infection linked to exacerbated inflammation and high mycobacterial burden. The lungs of infected IRG1-deficient mice displayed large areas of necrotizing granulomatous inflammation and neutrophil infiltration, accompanied by reduced levels of B and T lymphocytes and increased levels of alveolar and interstitial macrophage populations, compared to their wild type counterparts. Therefore, our findings demonstrate that IRG1 is a major player in controlling the acute phase of Mtb infection with a specific effect on pathogenic mycobacteria.

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Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection

Cited by 222 publications

References 21 publications

Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO‐1 signaling pathway

Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO‐1 signaling pathway

Itaconate: an emerging determinant of inflammation in activated macrophages

IRG1 controls host responses to restrict Mycobacterium tuberculosis infection

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