| First Author | Chen X | Year | 2022 |
| Journal | Nat Immunol | Volume | 23 |
| Issue | 7 | Pages | 1063-1075 |
| PubMed ID | 35668320 | Mgi Jnum | J:335105 |
| Mgi Id | MGI:7377820 | Doi | 10.1038/s41590-022-01231-0 |
| Citation | Chen X, et al. (2022) pH sensing controls tissue inflammation by modulating cellular metabolism and endo-lysosomal function of immune cells. Nat Immunol 23(7):1063-1075 |
| abstractText | Extracellular acidification occurs in inflamed tissue and the tumor microenvironment; however, a systematic study on how pH sensing contributes to tissue homeostasis is lacking. In the present study, we examine cell type-specific roles of the pH sensor G protein-coupled receptor 65 (GPR65) and its inflammatory disease-associated Ile231Leu-coding variant in inflammation control. GPR65 Ile231Leu knock-in mice are highly susceptible to both bacterial infection-induced and T cell-driven colitis. Mechanistically, GPR65 Ile231Leu elicits a cytokine imbalance through impaired helper type 17 T cell (TH17 cell) and TH22 cell differentiation and interleukin (IL)-22 production in association with altered cellular metabolism controlled through the cAMP-CREB-DGAT1 axis. In dendritic cells, GPR65 Ile231Leu elevates IL-12 and IL-23 release at acidic pH and alters endo-lysosomal fusion and degradation capacity, resulting in enhanced antigen presentation. The present study highlights GPR65 Ile231Leu as a multistep risk factor in intestinal inflammation and illuminates a mechanism by which pH sensing controls inflammatory circuits and tissue homeostasis. |
