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.

细胞外酸化发生在发炎组织和肿瘤微环境中；然而，目前还缺乏关于 pH 传感如何促进组织稳态的系统研究。在本研究中，我们研究了 pH 传感器 G 蛋白偶联受体 65 (GPR65) 及其炎症性疾病相关 Ile231Leu 编码变体在炎症控制中的细胞类型特异性作用。 GPR65 Ile231Leu 敲入小鼠对细菌感染诱导的结肠炎和 T 细胞驱动的结肠炎高度敏感。从机制上讲，GPR65 Ile231Leu 通过受损的辅助型 17 T 细胞（ _TH 17 细胞）和 T _H 22 细胞分化和白细胞介素 (IL)-22 的产生引起细胞因子失衡，并与通过 cAMP-CREB-DGAT1 轴控制的细胞代谢改变相关。 。在树突状细胞中，GPR65 Ile231Leu 在酸性 pH 条件下提高 IL-12 和 IL-23 的释放，并改变内溶酶体融合和降解能力，从而增强抗原呈递。本研究强调 GPR65 Ile231Leu 作为肠道炎症的多级危险因素，并阐明 pH 传感控制炎症回路和组织稳态的机制。