pH sensing controls tissue inflammation by modulating cellular metabolism and endo-lysosomal function of immune cells.
Nat Immunol
; 23(7): 1063-1075, 2022 07.
Article
in En
| MEDLINE
| ID: mdl-35668320
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Colitis
/
Receptors, G-Protein-Coupled
Type of study:
Risk_factors_studies
Limits:
Animals
Language:
En
Journal:
Nat Immunol
Journal subject:
ALERGIA E IMUNOLOGIA
Year:
2022
Type:
Article
Affiliation country:
United States