pH sensing controls tissue inflammation by modulating cellular metabolism and endo-lysosomal function of immune cells

Xiangjun Chen; Alok Jaiswal; Zachary Costliow; Paula Herbst; Elizabeth A Creasey; Noriko Oshiro-Rapley; Mark J Daly; Kimberly L Carey; Daniel B Graham; Ramnik J Xavier

doi:10.1038/s41590-022-01231-0

pH sensing controls tissue inflammation by modulating cellular metabolism and endo-lysosomal function of immune cells

Nat Immunol. 2022 Jul;23(7):1063-1075. doi: 10.1038/s41590-022-01231-0. Epub 2022 Jun 6.

Authors

Xiangjun Chen^{1

2

3

4}, Alok Jaiswal¹, Zachary Costliow¹, Paula Herbst^{2

3}, Elizabeth A Creasey^{1

2

3}, Noriko Oshiro-Rapley^{1

2

3

4}, Mark J Daly^{1

5

6}, Kimberly L Carey¹, Daniel B Graham^{1

2

3

4

7}, Ramnik J Xavier^{8

9

10

11}

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA.
³ Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
⁴ Experimental Medicine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Institute for Molecular Medicine Finland, Helsinki, Finland.
⁷ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA, USA. xavier@molbio.mgh.harvard.edu.
⁹ Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA. xavier@molbio.mgh.harvard.edu.
¹⁰ Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA. xavier@molbio.mgh.harvard.edu.
¹¹ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. xavier@molbio.mgh.harvard.edu.

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 (T_H17 cell) and T_H22 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Colitis* / metabolism
Hydrogen-Ion Concentration
Inflammation / metabolism
Lysosomes / metabolism
Mice
Receptors, G-Protein-Coupled* / genetics
Receptors, G-Protein-Coupled* / metabolism
Th17 Cells / metabolism

Substances

Receptors, G-Protein-Coupled

Abstract

Publication types

MeSH terms

Substances

Grants and funding