The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response
Yi-Rong Zeng, … , Dan Ye, Pu Wang
Yi-Rong Zeng, … , Dan Ye, Pu Wang
Published March 15, 2023
Citation Information: J Clin Invest. 2023;133(6):e160463. https://doi.org/10.1172/JCI160463.
View: Text | PDF
Research Article Metabolism

The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response

Abstract

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.

Authors

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

×

Figure 5

Depletion of either Oxgr1 or Irg1 disrupts the clearance of respiratory bacteria.

Options: View larger image (or click on image) Download as PowerPoint
Depletion of either Oxgr1 or Irg1 disrupts the clearance of respiratory ...
(A and B) Anesthetized mice of the indicated genotype (n = 4–10 per group) were intranasally administrated the P. aeruginosa strain PAO1 (1 × 107 CFU). BAL and lung tissue were collected 12 hours after infection. Representative images of PAO1 colonies on CTAB-selective plates after overnight culturing of BAL and lung from infected mice (dilution: 104-fold) (A) and quantification of CFU (B) are shown. *P < 0.05 and **P < 0.01, by 1-way ANOVA. Data indicate the mean ± SEM. (C and D) Anesthetized mice of the indicated genotype (n = 4–10 per group) were intranasally administrated 20 μL saline containing PAO1 (1 × 107 CFU) with or without 1 mM ITA. The CFU in BAL (C) and lung tissues (D) were quantified. **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA. Data indicate the mean ± SEM.