Itaconate Suppresses the Activation of Mitochondrial NLRP3 Inflammasome and Oxidative Stress in Allergic Airway Inflammation
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 ef...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/12/2/489 |
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| author | Qiu-Meng Xie Ning Chen Si-Ming Song Cui-Cui Zhao Ya Ruan Jia-Feng Sha Qian Liu Xu-Qin Jiang Guang-He Fei Hui-Mei Wu |
| author_facet | Qiu-Meng Xie Ning Chen Si-Ming Song Cui-Cui Zhao Ya Ruan Jia-Feng Sha Qian Liu Xu-Qin Jiang Guang-He Fei Hui-Mei Wu |
| author_sort | Qiu-Meng Xie |
| collection | DOAJ |
| description | 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 <i>Irg1</i><sup>−/−</sup> 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 <i>Irg1</i> mRNA/protein expression and itaconate production in the lung were significantly induced by OVA. Itaconate ameliorated while <i>Irg1</i> 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. |
| first_indexed | 2024-03-11T09:14:03Z |
| format | Article |
| id | doaj.art-6fd9baf345d54be1a916f8361a71c4c1 |
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| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-11T09:14:03Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-6fd9baf345d54be1a916f8361a71c4c12023-11-16T18:48:57ZengMDPI AGAntioxidants2076-39212023-02-0112248910.3390/antiox12020489Itaconate Suppresses the Activation of Mitochondrial NLRP3 Inflammasome and Oxidative Stress in Allergic Airway InflammationQiu-Meng Xie0Ning Chen1Si-Ming Song2Cui-Cui Zhao3Ya Ruan4Jia-Feng Sha5Qian Liu6Xu-Qin Jiang7Guang-He Fei8Hui-Mei Wu9Anhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei 230022, ChinaAnhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei 230022, ChinaAnhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei 230022, ChinaAnhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei 230022, ChinaAnhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei 230022, ChinaAnhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei 230022, ChinaDivision of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, ChinaDivision of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, ChinaAnhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei 230022, ChinaAnhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei 230022, ChinaItaconate 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 <i>Irg1</i><sup>−/−</sup> 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 <i>Irg1</i> mRNA/protein expression and itaconate production in the lung were significantly induced by OVA. Itaconate ameliorated while <i>Irg1</i> 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.https://www.mdpi.com/2076-3921/12/2/489allergic airway inflammationitaconateIrg1alveolar macrophagemitochondrialNLRP3 inflammasome |
| spellingShingle | Qiu-Meng Xie Ning Chen Si-Ming Song Cui-Cui Zhao Ya Ruan Jia-Feng Sha Qian Liu Xu-Qin Jiang Guang-He Fei Hui-Mei Wu Itaconate Suppresses the Activation of Mitochondrial NLRP3 Inflammasome and Oxidative Stress in Allergic Airway Inflammation Antioxidants allergic airway inflammation itaconate Irg1 alveolar macrophage mitochondrial NLRP3 inflammasome |
| title | Itaconate Suppresses the Activation of Mitochondrial NLRP3 Inflammasome and Oxidative Stress in Allergic Airway Inflammation |
| title_full | Itaconate Suppresses the Activation of Mitochondrial NLRP3 Inflammasome and Oxidative Stress in Allergic Airway Inflammation |
| title_fullStr | Itaconate Suppresses the Activation of Mitochondrial NLRP3 Inflammasome and Oxidative Stress in Allergic Airway Inflammation |
| title_full_unstemmed | Itaconate Suppresses the Activation of Mitochondrial NLRP3 Inflammasome and Oxidative Stress in Allergic Airway Inflammation |
| title_short | Itaconate Suppresses the Activation of Mitochondrial NLRP3 Inflammasome and Oxidative Stress in Allergic Airway Inflammation |
| title_sort | itaconate suppresses the activation of mitochondrial nlrp3 inflammasome and oxidative stress in allergic airway inflammation |
| topic | allergic airway inflammation itaconate Irg1 alveolar macrophage mitochondrial NLRP3 inflammasome |
| url | https://www.mdpi.com/2076-3921/12/2/489 |
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