4-Octyl itaconate attenuates glycemic deterioration by regulating macrophage polarization in mouse models of type 1 diabetes DOI Creative Commons
Sunyue He, Yuchen Zhao, Guoxing Wang

et al.

Molecular Medicine, Journal Year: 2023, Volume and Issue: 29(1)

Published: March 14, 2023

Abstract Background Pancreatic beta cell dysfunction and activated macrophage infiltration are early features in type 1 diabetes pathogenesis. A tricarboxylic acid cycle metabolite that can strongly activate NF-E2-related factor 2 (Nrf2) macrophages, itaconate is important a series of inflammatory-associated diseases via anti-inflammatory antioxidant properties. However, its role unclear. We used 4-octyl (OI), the cell-permeable derivate, to explore preventative therapeutic effects mouse models potential mechanism phenotype reprogramming. Methods The streptozotocin (STZ)-induced spontaneous autoimmune were evaluate OI, which performed by measuring blood glucose, insulin level, pro- cytokine secretion, histopathology examination, flow cytometry, islet proteomics. protective effect OI examined peritoneal macrophages isolated from STZ-induced diabetic mice co-cultured MIN6 cells with OI-pre-treated inflammatory vitro. Moreover, status peripheral mononuclear (PBMCs) patients was evaluated after treatment. Results ameliorated glycemic deterioration, increased systemic improved glucose metabolism non-obese (NOD) mice. intervention significantly restored insulitis function. did not alter count but downregulated proportion M1 macrophages. Additionally, inhibited MAPK activation attenuate response, eventually improving Furthermore, we detected higher IL-1β production upon lipopolysaccharide stimulation PBMCs patients, attenuated Conclusions These results provided first evidence date prevent progression excessive inflammation, predominantly mediated restricting polarization diabetes.

Language: Английский

Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury DOI Creative Commons
Ruyuan He, Bohao Liu, Rui Xiong

et al.

Cell Death Discovery, Journal Year: 2022, Volume and Issue: 8(1)

Published: Feb. 2, 2022

Itaconate, a metabolite produced during inflammatory macrophage activation, has been extensively described to be involved in immunoregulation, oxidative stress, and lipid peroxidation. As form of iron hydroperoxide-dependent regulated cell death, ferroptosis plays critical role sepsis-induced acute lung injury (ALI). However, the relationship between itaconate remains unclear. This study aims explore regulatory on ALI. In vivo experiments, mice were injected with LPS (10 mg/kg) for 12 h generate experimental sepsis models. Differential gene expression analysis indicated that genes associated existed significant differences after pretreatment. 4-octyl (4-OI), cell-permeable derivative endogenous itaconate, can significantly alleviate injury, increase LPS-induced levels glutathione peroxidase 4 (GPX4) reduce prostaglandin-endoperoxide synthase 2 (PTGS2), malonaldehyde (MDA), ROS. vitro experiments showed both 4-OI ferrostatin-1 inhibited peroxidation THP-1 macrophage. Mechanistically, we identified GPX4-dependent through increased accumulation activation Nrf2. The silence Nrf2 abolished inhibition from cells. Additionally, protection ALI was Nrf2-knockout mice. We concluded one mechanisms contributing Itaconate is promising as therapeutic candidate against inhibiting ferroptosis.

Language: Английский

Citations

172
Macrophage Polarization and Reprogramming in Acute Inflammation: A Redox Perspective DOI Creative Commons
Salvador Pérez, Sergio Rius‐Pérez

Antioxidants, Journal Year: 2022, Volume and Issue: 11(7), P. 1394 - 1394

Published: July 19, 2022

Macrophage polarization refers to the process by which macrophages can produce two distinct functional phenotypes: M1 or M2. The balance between both strongly affects progression of inflammatory disorders. Here, we review how redox signals regulate macrophage and reprogramming during acute inflammation. In M1, augment NADPH oxidase isoform 2 (NOX2), inducible nitric oxide synthase (iNOS), synaptotagmin-binding cytoplasmic RNA interacting protein (SYNCRIP), tumor necrosis factor receptor-associated 6 increase oxygen nitrogen reactive species, triggers response, phagocytosis, cytotoxicity. M2, down-regulate NOX2, iNOS, SYNCRIP, and/or up-regulate arginase superoxide dismutase type 1, counteract oxidative nitrosative stress, favor anti-inflammatory tissue repair responses. M2 exhibit different metabolic profiles, are tightly regulated mechanisms. Oxidative stress sustain phenotype activating glycolysis lipid biosynthesis, but inhibiting tricarboxylic acid cycle phosphorylation. This profile is reversed in because changes state. Therefore, new therapies based on mechanisms have emerged treat inflammation with positive results, highlights relevance signaling as a master regulator reprogramming.

Language: Английский

Citations

159
Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response DOI
Dylan G. Ryan,

Elena V. Knatko,

Alva M. Casey

et al.

iScience, Journal Year: 2022, Volume and Issue: 25(2), P. 103827 - 103827

Published: Jan. 30, 2022

Language: Английский

Citations

79
Itaconate in host inflammation and defense DOI
Dan Ye, Pu Wang, Leilei Chen

et al.

Trends in Endocrinology and Metabolism, Journal Year: 2024, Volume and Issue: 35(7), P. 586 - 606

Published: March 5, 2024

Language: Английский

Citations

17
Irg1/itaconate metabolic pathway is a crucial determinant of dendritic cells immune-priming function and contributes to resolute allergen-induced airway inflammation DOI Creative Commons
Anil K. Jaiswal, Jyoti Yadav, Sangeet Makhija

et al.

Mucosal Immunology, Journal Year: 2021, Volume and Issue: 15(2), P. 301 - 313

Published: Oct. 20, 2021

Itaconate is produced from the mitochondrial TCA cycle enzyme aconitase decarboxylase (encoded by immune responsive gene1; Irg1) that exerts immunomodulatory function in myeloid cells. However, role of Irg1/itaconate pathway dendritic cells (DC)-mediated airway inflammation and adaptive immunity to inhaled allergens, which are primary antigen-presenting allergic asthma, remains largely unknown. House dust mite (HDM)-challenged Irg1−/− mice displayed increases eosinophilic inflammation, mucous cell metaplasia, Th2 cytokine production with a mechanism involving impaired antigen presentations DC. Adoptive transfer HDM-pulsed DC Irg1-deficient into naïve WT induced similar phenotype elevated type 2 sensitization. Untargeted metabolite analysis revealed itaconate as one most abundant polar metabolites potentially suppress oxidative damage. Furthermore, effect was translated vivo, where intranasal administration 4-octyl 4-OI following priming attenuated manifestations HDM-induced disease response. Taken together, these data demonstrated for first time direct regulatory development suggest possible therapeutic target modulating asthma.

Language: Английский

Citations

60
Four-Octyl itaconate ameliorates periodontal destruction via Nrf2-dependent antioxidant system DOI Creative Commons

Liangjing Xin,

Fuyuan Zhou,

Chuangwei Zhang

et al.

International Journal of Oral Science, Journal Year: 2022, Volume and Issue: 14(1)

Published: May 31, 2022

Abstract Periodontitis is a widespread oral disease characterized by continuous inflammation of the periodontal tissue and an irreversible alveolar bone loss, which eventually leads to tooth loss. Four-octyl itaconate (4-OI) cell-permeable derivative has been recognized as promising therapeutic target for treatment inflammatory diseases. Here, we explored, first time, protective effect 4-OI on inhibiting destruction, ameliorating local inflammation, underlying mechanism in periodontitis. Here showed that ameliorates induced lipopolysaccharide microenvironment. can also significantly alleviate loss via Nrf2 activation observed samples from experimental periodontitis C57BL/6 mice. This was further confirmed silencing blocked antioxidant downregulating expression downstream enzymes. Additionally, molecular docking simulation indicated possible under activation. Also, −/− mice, did not protect against dysfunction due periodontitis, underlined importance mediated treatment. Our results attenuates oxidative stress disassociation KEAP1-Nrf2 signaling cascade. Taken together, administration offers clinical potential inhibit ameliorate more predictable

Language: Английский

Citations

45
Effects of Metabolism on Macrophage Polarization Under Different Disease Backgrounds DOI Creative Commons
Jiaxue Sun, Xianghong Xu, Liping Jin

et al.

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: July 14, 2022

Macrophages are versatile immune cells associated with various diseases, and their phenotypes functions change on the basis of surrounding environments. Reprogramming metabolism is required for proper polarization macrophages. This review will focus basic metabolic pathways, effects key enzymes specific products, relationships between cellular macrophage in different diseases potential prospect therapy targeted enzymes. In particular, types characteristics macrophages at maternal-fetal interface a successful conception be discussed.

Language: Английский

Citations

43
Immune-responsive gene 1/itaconate activates nuclear factor erythroid 2-related factor 2 in microglia to protect against spinal cord injury in mice DOI Creative Commons

Libin Ni,

Jian Xiao, Di Zhang

et al.

Cell Death and Disease, Journal Year: 2022, Volume and Issue: 13(2)

Published: Feb. 10, 2022

Abstract The pathophysiology of spinal cord injury (SCI) involves primary and secondary injury. Secondary is a major target for SCI therapy, whereas microglia play an important role in immunoresponsive gene 1 (Irg-1) has been recorded as one the most significantly upregulated genes tissues chip data; however, its remains unclear. This study aims to illustrate Irg-1 well regulated metabolite itaconate SCI. It was demonstrated that expression increased mice stimulated by lipopolysaccharides (LPS). also shown overexpression may suppress LPS-induced inflammation microglia, while these protective effects were attenuated Nrf2 silencing. In vivo, neuroinflammation improve motor function recovery. Furthermore, treatment with similar suppressive vitro improved recovery vivo. conclusion, current shows are involved process SCI, either or provide promising strategy

Language: Английский

Citations

40
4-octyl itaconate ameliorates alveolar macrophage pyroptosis against ARDS via rescuing mitochondrial dysfunction and suppressing the cGAS/STING pathway DOI

Yutong Wu,

Wenting Xu, Zheng Li

et al.

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 118, P. 110104 - 110104

Published: March 31, 2023

Language: Английский

Citations

31
Targeting thromboinflammation in antiphospholipid syndrome DOI Creative Commons
Dorien M. Salet, Siroon Bekkering, Saskia Middeldorp

et al.

Journal of Thrombosis and Haemostasis, Journal Year: 2023, Volume and Issue: 21(4), P. 744 - 757

Published: Jan. 25, 2023

Antiphospholipid syndrome (APS) is a systemic autoimmune disease, where persistent presence of antiphospholipid antibodies (aPL) leads to thrombotic and obstetric complications. APS paradigmatic thromboinflammatory disease. Thromboinflammation pathophysiological mechanism coupling inflammation thrombosis, which contributes the pathophysiology cardiovascular can serve as model unravel mechanisms thromboinflammation relationship between innate immune cells thrombosis. Monocytes are activated by aPL into proinflammatory procoagulant phenotype, producing cytokines such tumor necrosis factor α, interleukin 6, well tissue factor. Important cellular signaling pathways involved NF-κB-pathway, mammalian target rapamycin (mTOR) signaling, NOD-, LRR-, pyrin domain-containing protein 3 inflammasome. All these may future therapeutic targets. Neutrophils produce neutrophil extracellular traps in response aPL, this Thrombosis also stems from increased interaction neutrophils with endothelial through P-selectin glycoprotein ligand-1. NETosis be targeted not only several experimental therapeutics, DNase, but redirection current therapies defibrotide antiplatelet agent dipyridamole. Activation platelets phenotype. Platelet-leukocyte interactions increased, possibly mediated levels soluble CD40-ligand. Platelet-directed treatment options involve inhibition platelet receptors mTOR inhibition. This review discusses underlying that present targetable options, some generalizable other diseases.

Language: Английский

Citations

30