The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response
Pathogens and inflammatory conditions rapidly induce the expression of immune-responsive gene 1 (IRG1) in cells of myeloid lineage. IRG1 encodes an aconitate decarboxylase (ACOD1) that produces the immunomodulatory metabolite itaconate (ITA). In addition to rapid intracellular accumulation, ITA is a...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2023-03-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI160463 |
| _version_ | 1797634485270872064 |
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| author | Yi-Rong Zeng Jun-Bin Song Dezheng Wang Zi-Xuan Huang Cheng Zhang Yi-Ping Sun Gang Shu Yue Xiong Kun-Liang Guan Dan Ye Pu Wang |
| author_facet | Yi-Rong Zeng Jun-Bin Song Dezheng Wang Zi-Xuan Huang Cheng Zhang Yi-Ping Sun Gang Shu Yue Xiong Kun-Liang Guan Dan Ye Pu Wang |
| author_sort | Yi-Rong Zeng |
| collection | DOAJ |
| description | Pathogens and inflammatory conditions rapidly induce the expression of immune-responsive gene 1 (IRG1) in cells of myeloid lineage. IRG1 encodes an aconitate decarboxylase (ACOD1) that produces the immunomodulatory metabolite itaconate (ITA). In addition to rapid intracellular accumulation, ITA is also secreted from the cell, but whether secreted ITA functions as a signaling molecule is unclear. Here, we identified ITA as an orthosteric agonist of the GPCR OXGR1, with an EC50 of approximately 0.3 mM, which was in the same range as the physiological concentration of extracellular ITA upon macrophage activation. ITA activated OXGR1 to induce Ca2+ mobilization, ERK phosphorylation, and endocytosis of the receptor. In a mouse model of pulmonary infection with bacterial Pseudomonas aeruginosa, ITA stimulated Oxgr1-dependent mucus secretion and transport in respiratory epithelium, the primary innate defense mechanism of the airway. Our study thus identifies ITA as a bona fide ligand for OXGR1 and the ITA/OXGR1 paracrine signaling pathway during the pulmonary innate immune response. |
| first_indexed | 2024-03-11T12:08:28Z |
| format | Article |
| id | doaj.art-1a83b2ed5533492cbb026c861234e573 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:08:28Z |
| publishDate | 2023-03-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-1a83b2ed5533492cbb026c861234e5732023-11-07T16:20:04ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-03-011336The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune responseYi-Rong ZengJun-Bin SongDezheng WangZi-Xuan HuangCheng ZhangYi-Ping SunGang ShuYue XiongKun-Liang GuanDan YePu WangPathogens and inflammatory conditions rapidly induce the expression of immune-responsive gene 1 (IRG1) in cells of myeloid lineage. IRG1 encodes an aconitate decarboxylase (ACOD1) that produces the immunomodulatory metabolite itaconate (ITA). In addition to rapid intracellular accumulation, ITA is also secreted from the cell, but whether secreted ITA functions as a signaling molecule is unclear. Here, we identified ITA as an orthosteric agonist of the GPCR OXGR1, with an EC50 of approximately 0.3 mM, which was in the same range as the physiological concentration of extracellular ITA upon macrophage activation. ITA activated OXGR1 to induce Ca2+ mobilization, ERK phosphorylation, and endocytosis of the receptor. In a mouse model of pulmonary infection with bacterial Pseudomonas aeruginosa, ITA stimulated Oxgr1-dependent mucus secretion and transport in respiratory epithelium, the primary innate defense mechanism of the airway. Our study thus identifies ITA as a bona fide ligand for OXGR1 and the ITA/OXGR1 paracrine signaling pathway during the pulmonary innate immune response.https://doi.org/10.1172/JCI160463Metabolism |
| spellingShingle | Yi-Rong Zeng Jun-Bin Song Dezheng Wang Zi-Xuan Huang Cheng Zhang Yi-Ping Sun Gang Shu Yue Xiong Kun-Liang Guan Dan Ye Pu Wang The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response The Journal of Clinical Investigation Metabolism |
| title | The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response |
| title_full | The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response |
| title_fullStr | The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response |
| title_full_unstemmed | The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response |
| title_short | The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response |
| title_sort | immunometabolite itaconate stimulates oxgr1 to promote mucociliary clearance during the pulmonary innate immune response |
| topic | Metabolism |
| url | https://doi.org/10.1172/JCI160463 |
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