Itaconate suppresses atherosclerosis by activating a Nrf2-dependent antiinflammatory response in macrophages in mice DOI Creative Commons
Jianrui Song, Yanling Zhang, Ryan A. Frieler

et al.

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 134(3)

Published: Dec. 12, 2023

Itaconate has emerged as a critical immunoregulatory metabolite. Here, we examined the therapeutic potential of itaconate in atherosclerosis. We found that both and enzyme synthesizes it, aconitate decarboxylase 1 (Acod1, also known "immune-responsive gene 1"/IRG1) are upregulated during atherogenesis mice. Deletion Acod1 myeloid cells exacerbated inflammation atherosclerosis vivo resulted an elevated frequency specific subset M1-polarized proinflammatory macrophages atherosclerotic aorta. Importantly, levels were inversely correlated with clinical occlusion human aorta specimens. Treating mice derivative 4-ocytyl attenuated induced by high cholesterol. Mechanistically, antioxidant transcription factor, Nuclear factor erythroid-2 Related Factor 2 (Nrf2) was required for to suppress macrophage activation oxidized lipids vitro decrease lesion areas vivo. Overall, our work shows suppresses inducing Nrf2-dependent inhibition responses macrophages. Activation pathway may represent important approach treat

Language: Английский

Itaconic acid underpins hepatocyte lipid metabolism in non-alcoholic fatty liver disease in male mice DOI Creative Commons
Jonathan M. Weiss, Erika M. Palmieri, Marieli Gonzalez-Cotto

et al.

Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(6), P. 981 - 995

Published: June 12, 2023

Abstract Itaconate, the product of decarboxylation cis -aconitate, regulates numerous biological processes. We and others have revealed itaconate as a regulator fatty acid β-oxidation, generation mitochondrial reactive oxygen species metabolic interplay between resident macrophages tumors. In present study, we show that itaconic is upregulated in human non-alcoholic steatohepatitis mouse model liver disease. Male mice deficient gene responsible for production (immunoresponsive (Irg)-1) exacerbated lipid accumulation liver, glucose insulin intolerance mesenteric fat deposition. Treatment with derivative, 4-octyl itaconate, reverses dyslipidemia associated high-fat diet feeding. Mechanistically, treatment primary hepatocytes reduces increases their oxidative phosphorylation manner dependent upon oxidation. propose whereby macrophage-derived acts trans to modulate liver’s ability metabolize acids.

Language: Английский

Citations

46
An Antioxidative and Active Shrinkage Hydrogel Integratedly Promotes Re‐Epithelization and Skin Constriction for Enhancing Wound Closure DOI Creative Commons
Jiacheng Sun, Jia Wang,

Hedong Qi

et al.

Advanced Materials, Journal Year: 2024, Volume and Issue: 36(21)

Published: Feb. 9, 2024

Abstract Delayed re‐epithelization and weakened skin contractions are the two primary factors that hinder wound closure in large‐scale acute or chronic wounds. However, effective strategies for targeting these aspects concurrently still lacking. Herein, an antioxidative active‐shrinkage hydrogel (AHF@AS Gel) is constructed can integratedly promote constriction to accelerate diabetic closure. The AHF@AS Gel encapsulated by amino‐ hydroxyl‐modified C 70 fullerene (AHF) a thermosensitive active shrinkage (AS Gel). Specifically, AHF relieves overactivated inflammation, prevents cellular apoptosis, promotes fibroblast migration vitro reducing excessive reactive oxygen species (ROS). Notably, achieved ≈2.7‐fold ≈1.7‐fold better wounds wounds, respectively, significantly contributing promotion of Using proteomic profiling mechanistic studies, it identified efficiently promoted transition inflammatory proliferative phases remodeling phase. demonstrated AS alone activates mechanosensitive epidermal growth factor receptor/Akt (EGFR/Akt) pathway cell proliferation. offers comprehensive strategy via biochemistry regulation integrating with mechanical forces stimulation.

Language: Английский

Citations

45
Targeting immunometabolism against acute lung injury DOI Open Access

Li Ning,

Zou Shishi,

Bo Wang

et al.

Clinical Immunology, Journal Year: 2023, Volume and Issue: 249, P. 109289 - 109289

Published: March 12, 2023

Language: Английский

Citations

42
Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells DOI Creative Commons
Theresa Ramalho, Patrícia A. Assis,

Ogooluwa Ojelabi

et al.

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(3), P. 484 - 497.e6

Published: Feb. 6, 2024

Severe forms of malaria are associated with systemic inflammation and host metabolism disorders; however, the interplay between these outcomes is poorly understood. Using a Plasmodium chabaudi model malaria, we demonstrate that interferon (IFN) γ boosts glycolysis in splenic monocyte-derived dendritic cells (MODCs), leading to itaconate accumulation disruption TCA cycle. Increased levels reduce mitochondrial functionality, which associates organellar nucleic acid release MODC restraint. We hypothesize dysfunctional mitochondria degraded DNA into cytosol. Once sensitized, activation IRF3 IRF7 promotes expression IFN-stimulated genes checkpoint markers. Indeed, depletion STING-IRF3/IRF7 axis reduces PD-L1 expression, enabling CD8+ T control parasite proliferation. In summary, caused by MODCs leads suppressive effect cells, enhances parasitemia. provide evidence ACOD1 potential targets for adjunct antimalarial therapy.

Language: Английский

Citations

27
The IRG1–itaconate axis protects from cholesterol-induced inflammation and atherosclerosis DOI Creative Commons
Yannick Cyr, Fazli Bozal, José Gabriel Barcia Durán

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(15)

Published: April 2, 2024

Atherosclerosis is fueled by a failure to resolve lipid-driven inflammation within the vasculature that drives plaque formation. Therapeutic approaches reverse atherosclerotic are needed address rising global burden of cardiovascular disease (CVD). Recently, metabolites have gained attention for their immunomodulatory properties, including itaconate, which generated from tricarboxylic acid-intermediate cis-aconitate enzyme Immune Responsive Gene 1 (IRG1/ACOD1). Here, we tested therapeutic potential IRG1–itaconate axis human atherosclerosis. Using single-cell RNA sequencing (scRNA-seq), found IRG1 up-regulated in coronary lesions compared patient-matched healthy vasculature, and mouse models atherosclerosis, where it primarily expressed monocytes, macrophages, neutrophils. Global or hematopoietic Irg1 -deficiency mice increases atherosclerosis burden, macrophage lipid content, expression proatherosclerotic cytokine interleukin (IL)-1β. Mechanistically, absence increased accumulation, accelerated via neutrophil extracellular trap (NET) formation NET-priming NLRP3-inflammasome resulting IL-1β release. Conversely, supplementation –itaconate using 4-octyl itaconate (4-OI) beneficially remodeled advanced plaques reduced lesional levels mice. To investigate effects 4-OI humans, leveraged an ex vivo systems-immunology approach CVD drug discovery. CyTOF scRNA-seq peripheral blood mononuclear cells treated with plasma patients, showed attenuates proinflammatory phospho-signaling mediates anti-inflammatory rewiring populations. Our data highlight relevance pursuing as humans.

Language: Английский

Citations

27
Multifunctional Ac@ZIF-8/AgNPs nanoplatform with pH-responsive and ROS scavenging antibacterial properties promotes infected wound healing DOI

Yipeng Pang,

Maofang Zhao,

Yuhan Xie

et al.

Chemical Engineering Journal, Journal Year: 2024, Volume and Issue: 489, P. 151485 - 151485

Published: April 20, 2024

Language: Английский

Citations

21
Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies DOI Creative Commons
Saeed Daneshmandi, Jee Eun Choi, Yan Qi

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 30, 2024

Language: Английский

Citations

16
Inhibition of Mitochondrial Succinate Dehydrogenase with Dimethyl Malonate Promotes M2 Macrophage Polarization by Enhancing STAT6 Activation DOI
Chaowen He, Pengfei Chen, Ning Li

et al.

Inflammation, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Language: Английский

Citations

3
Itaconate transporter SLC13A3 confers immunotherapy resistance via alkylation-mediated stabilization of PD-L1 DOI Creative Commons
Yizeng Fan,

Weichao Dan,

Yuzhao Wang

et al.

Cell Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Itaconate is a metabolite catalyzed by cis-aconitate decarboxylase (ACOD1), which mainly produced activated macrophages and secreted into the extracellular environment to exert complex bioactivity. In tumor microenvironment, itaconate concentrated induces an immunosuppressive response. However, whether can be taken up cells its mechanism of action remain largely unclear. Here, we identified solute carrier family 13 member 3 (SLC13A3) as key protein transporting cells, where it elevates programmed cell death ligand 1 (PD-L1) levels decreases expression immunostimulatory molecules, thereby promoting immune evasion. Mechanistically, alkylates cysteine 272 residue on PD-L1, antagonizing PD-L1 ubiquitination degradation. Consequently, SLC13A3 inhibition enhances efficacy anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) immunotherapy improves overall survival rate in syngeneic mouse models. Collectively, our findings transporter revealed immunomodulatory role, providing combinatorial strategies overcome resistance tumors.

Language: Английский

Citations

3
Nonresolving inflammation redux DOI Creative Commons
Carl Nathan

Immunity, Journal Year: 2022, Volume and Issue: 55(4), P. 592 - 605

Published: April 1, 2022

Language: Английский

Citations

65