Itaconate Suppresses the Activation of Mitochondrial NLRP3 Inflammasome and Oxidative Stress in Allergic Airway Inflammation

Author:

Xie Qiu-Meng123,Chen Ning123,Song Si-Ming123,Zhao Cui-Cui123,Ruan Ya123,Sha Jia-Feng123,Liu Qian45,Jiang Xu-Qin45,Fei Guang-He123,Wu Hui-Mei123ORCID

Affiliation:

1. Anhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei 230022, China

2. Key Laboratory of Geriatric Molecular Medicine of Anhui Province, Jixi Road 218, Hefei 230022, China

3. Key Laboratory of Respiratory Disease Research and Medical Transformation of Anhui Province, Jixi Road 218, Hefei 230022, China

4. Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China

5. Department of Respiratory Medicine, The First Affiliated Hospital of University of Science and Technology of China, Hefei 230001, China

Abstract

Itaconate has emerged as a novel anti-inflammatory and antioxidative endogenous metabolite, yet its role in allergic airway inflammation (AAI) and the underlying mechanism remains elusive. Here, the itaconate level in the lung was assessed by High Performance Liquid Chromatography (HPLC), and the effects of the Irg1/itaconate pathway on AAI and alveolar macrophage (AM) immune responses were evaluated using an ovalbumin (OVA)-induced AAI model established by wild type (WT) and Irg1−/− mice, while the mechanism of this process was investigated by metabolomics analysis, mitochondrial/cytosolic protein fractionation and transmission electron microscopy in the lung tissues. The results demonstrated that the Irg1 mRNA/protein expression and itaconate production in the lung were significantly induced by OVA. Itaconate ameliorated while Irg1 deficiency augmented AAI, and this may be attributed to the fact that itaconate suppressed mitochondrial events such as NLRP3 inflammasome activation, oxidative stress and metabolic dysfunction. Furthermore, we identified that the Irg1/itaconate pathway impacted the NLRP3 inflammasome activation and oxidative stress in AMs. Collectively, our findings provide evidence for the first time, supporting the conclusion that in the allergic lung, the itaconate level is markedly increased, which directly regulates AMs’ immune responses. We therefore propose that the Irg1/itaconate pathway in AMs is a potential anti-inflammatory and anti-oxidative therapeutic target for AAI.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Anhui Province of China

Natural Science Research Project of Anhui Educational Committee

Foundation of Anhui Medical University

Publisher

MDPI AG

Subject

Cell Biology,Clinical Biochemistry,Molecular Biology,Biochemistry,Physiology

Reference58 articles.

1. GINA Executive and Science Committee (2022, May 03). Global Strategy for Asthma Management and Prevention 2021. Available online: https://ginasthma.org/gina-reports/.

2. The genetics of asthma and the promise of genomics-guided drug target discovery;Gosens;Lancet Respir. Med.,2020

3. Inhaled Corticosteroids Safety and Adverse Effects in Patients with Asthma;Heffler;J. Allergy Clin. Immunol. Pract.,2018

4. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production;Michelucci;Proc. Natl. Acad. Sci. USA,2013

5. Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation;Lampropoulou;Cell Metab.,2016

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