The STING1-MYD88 complex drives ACOD1/IRG1 expression and function in lethal innate immunity

Chen, Feng; Wu, Runliu; Liu, Jiao; Kang, Rui; Li, Jinbao; Tang, Daolin

doi:10.1016/j.isci.2022.104561

Cited by 18 publications

(9 citation statements)

References 82 publications

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“…These results are in agreement with previous reports where STING activation after TLR4 engagement induces ACOD1 expression (40).…”

Section: Discussionsupporting

confidence: 94%

“…Consistent with our observation in BMDM, inhibition of the STING pathway and STAT3/STAT4 also decreased ACOD1 induction. These results are in agreement with previous reports where STING activation after TLR4 engagement induces ACOD1 expression ( 40 ).…”

Section: Discussionsupporting

confidence: 94%

“…These results are in agreement with previous reports where STING activation after TLR4 engagement induces ACOD1 expression (40). SLE is a multisystem disease, and its clinical manifestations vary according to the organs involved .…”

Section: Discussionsupporting

confidence: 93%

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The aconitate decarboxylase 1/itaconate pathway modulates immune dysregulation and associates with cardiovascular disease markers in SLE

Patiño-Martinez,

Nakabo,

Jiang

et al. 2024

Preprint

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What is already known on this topicAconitate Decarboxylase 1 (ACOD1) is an enzyme involved in the synthesis of itaconate, a metabolite generated during the Krebs cycle.Itaconate has been identified as an immunomodulatory moleculeACOD1/Itaconate has been studied in the context of various inflammatory and autoimmune diseases, including sepsis, inflammatory bowel disease and rheumatoid arthritis. In these conditions, dysregulation of itaconate metabolism has been associated with altered immune responses and disease progression.What this study adds1.Upon stimulation with lupus-relevant stimuli, ACOD1 expression is induced in myeloid cells.2.IN an induced mouse model of lupus, ACOD1 knockout (Acod1-/-) mice exhibit exacerbated lupus-like symptoms, implicating dysregulation of this pathway in the induction and severity of autoimmunity features.3.Itaconate serum levels are decreased in SLE patients, compared to healthy individuals. This decrease is associated with specific perturbed cardiometabolic parameters and subclinical atherosclerosis, indicating that modulating dysregulation of the itaconate pathway could have therapeutic benefits in this disease.How this study might affect research, practice or policyGiven its immunomodulatory effects, ACOD1/itaconate and its derivatives may have potential therapeutic benefit for the treatment of autoimmune diseases. They may also serve as putative biomarkers of cardiovascular risk in this disease.ObjectiveThe Krebs cycle enzyme Aconitate Decarboxylase 1 (ACOD1) mediates itaconate synthesis in myeloid cells.. Previously, we reported that administration of 4-octyl itaconate abrogated lupus phenotype in mice. Here, we explore the role of the endogenous ACOD1/itaconate pathway in the development of murine lupus as well as their relevance in premature cardiovascular damage in SLE.MethodsWe characterized Acod1 protein expression in bone marrow-derived macrophages and human monocyte-derived macrophages, following a TLR7 agonist (imiquimod, IMQ). Wild type and Acod1-/-mice were exposed to topical IMQ for 5 weeks to induce an SLE phenotype and immune dysregulation was quantified. Itaconate serum levels were quantified in SLE patients and associated to cardiometabolic parameters and disease activity.ResultsACOD1 was induced in mouse bone marrow-derived macrophages (BMDM) and human monocyte-derived macrophages following in vitro TLR7 stimulation. This induction was partially dependent on type I Interferon receptor signaling and specific intracellular pathways. In the IMQ-induced mouse model of lupus, ACOD1 knockout (Acod1-/-) displayed disruptions of the splenic architecture, increased serum anti-dsDNA and proinflammatory cytokine levels, enhanced kidney immune complex deposition and proteinuria, when compared to the IMQ-treated WT mice. Consistent with these results,Acod1-/-BMDM exposed to IMQ showed higher proinflammatory features in vitro. Itaconate levels were decreased in SLE serum compared to healthy control sera, in association with specific perturbed cardiometabolic parameters and subclinical vascular disease.ConclusionThese findings suggest that the ACOD1/itaconate pathway plays important immunomodulatory and vasculoprotective roles in SLE, supporting the potential therapeutic role of itaconate analogs in autoimmune diseases.

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“…These results are in agreement with previous reports where STING activation after TLR4 engagement induces ACOD1 expression (40).…”

Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 94%

See 1 more Smart Citation

The aconitate decarboxylase 1/itaconate pathway modulates immune dysregulation and associates with cardiovascular disease markers in SLE

Patiño-Martinez,

Nakabo,

Jiang

et al. 2024

Preprint

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“…Expression of Irg1 in these isolated immune cells was higher during EAE compared to CFA control which was further validated by quantitative PCR ( Fig 1E-F ). Interestingly, we also observed the significant upregulation of Irg-1 at both mRNA and protein level in CD4 + T of EAE mice compared to control mice, earlier reports mainly about the Irg-1 expression in myeloid cells 12,20 . These sets of experiments suggest that itaconate levels are increased as a results of higher Irg1 expression in CNS during EAE, raising the question, if their elevated levels are protective or pathogenic.…”

Section: Resultssupporting

confidence: 69%

Immuno-Responsive Gene-1: A mitochondrial gene regulates pathogenic Th17 in CNS autoimmunity mouse model

Nematullah,

Fatma,

Rashid

et al. 2023

Preprint

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Pathogenic Th17 cells are crucial to CNS autoimmune diseases like multiple sclerosis (MS), though their control by endogenous mechanisms is unknown. RNAseq analysis of brain glial cells identified immuno-responsive gene 1 (Irg1), a mitochondrial-related enzyme-coding gene, as one of the highly upregulated gene under inflammatory conditions which were further validated in the spinal cord of animals with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Moreover,Irg1mRNA and protein levels in myeloid, CD4, and B cells were higher in the EAE group, raising questions about its function in CNS autoimmunity. We observed thatIrg1knockout (KO) mice exhibited severe EAE disease and greater mononuclear cell infiltration, including triple-positive CD4 cells expressing IL17a, GM-CSF, and IFNγ. Lack ofIrg1in macrophages led to higher levels of Class II expression and polarized myelin primed CD4 cells into pathogenic Th17 cells through the NLRP3/IL1β axis. Our findings show thatIrg1in macrophages plays an important role in the formation of pathogenic Th17 cells, emphasizing its potential as a therapy for autoimmune diseases, including MS.

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“…In turn, ACOD1-activaded macrophages produces itaconate with potential anti-inflammatory activity (Bambouskova et al, 2021 ). Chen et al ( 2022 ) studies using the sepsis model reported that STING mediates LPS-induced ACOD1 expression by binding to MyD88. They showed that the STING-MyD88 pathway mediates inducible ACOD1 expression in macrophages activated by TLR1, TRL2, TRL4, TRL5, or TLR6 ligands.…”

Section: Sting Paving the Way To Inflammatory Macrophagesmentioning

confidence: 99%

How the crosstalk between innate immune sensors and metabolic pathways affect the outcome of Brucella abortus infection?

Oliveira

Guimarães

2022

Front. Microbiol.

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The STING1-MYD88 complex drives ACOD1/IRG1 expression and function in lethal innate immunity

Cited by 18 publications

References 82 publications

The aconitate decarboxylase 1/itaconate pathway modulates immune dysregulation and associates with cardiovascular disease markers in SLE

The aconitate decarboxylase 1/itaconate pathway modulates immune dysregulation and associates with cardiovascular disease markers in SLE

Immuno-Responsive Gene-1: A mitochondrial gene regulates pathogenic Th17 in CNS autoimmunity mouse model

How the crosstalk between innate immune sensors and metabolic pathways affect the outcome of Brucella abortus infection?

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