pH sensing and inflammation: linking acidic microenvironments to immune reprogramming

As a critical variable of physiological homeostasis, pH has traditionally been regarded as a metabolic byproduct. However, accumulating evidence indicates that pH also functions as an active signaling cue capable of modulating the initiation and regulation of inflammation via proton-sensing receptors. Tissue acidification is widely observed across pathological conditions, including infection, ischemia, cancer, and chronic inflammatory diseases. Acidic microenvironments not only influence immune cell metabolism and effector functions but also promote the release of inflammatory mediators and contribute to tissue injury. The immune system harbors a diverse array of proton sensors, including proton-sensitive G protein-coupled receptors (GPCRs; e.g., GPR4, GPR65, GPR68), acid-sensing ion channels (ASICs), transient receptor potential (TRP) channels, intracellular pH sensors and pH-responsive regulatory factors, including BRD4, HIF-1α, SMAD5, and SREBP2. These sensors transduce local pH fluctuations into specific signaling cascades and gene expression programs, thereby reshaping inflammatory responses. In this review, we systematically summarize recent advances in understanding pH sensing in the regulation of inflammation. We focus on (i) the structural classes and distribution patterns of pH sensors, (ii) the molecular integration of acidic signals within inflammatory signaling networks and their transcriptional regulatory mechanisms, and (iii) the roles of pH sensing in immune homeostasis and pathological inflammation. Finally, we highlight emerging opportunities for identifying pH-based diagnostic biomarkers and developing targeted therapeutic interventions. Collectively, this work underscores the conceptual and translational significance of the "pH-sensor-inflammation" axis as an emerging paradigm in immune regulation.