Hypothesis pH sensing at the intersection of tissue homeostasis and inflammation, 2023, Stephanie Hajjar; Xu Zhou

pH sensing at the intersection of tissue homeostasis and inflammation
Stephanie Hajjar; Xu Zhou

pH is tightly maintained at cellular, tissue, and systemic levels, and altered pH – particularly in the acidic range – is associated with infection, injury, solid tumors, and physiological and pathological inflammation. However, how pH is sensed and regulated and how it influences immune responses remain poorly understood at the tissue level.

Applying conceptual frameworks of homeostatic and inflammatory circuitries, we categorize cellular and tissue components engaged in pH regulation, drawing parallels from established cases in physiology. By expressing various intracellular (pHi) and extracellular pH (pHe)-sensing receptors, the immune system may integrate information on tissue and cellular states into the regulation of homeostatic and inflammatory programs. We introduce the novel concept of resistance and adaptation responses to rationalize pH-dependent immunomodulation intertwined with homeostatic equilibrium and inflammatory control. We discuss emerging challenges and opportunities in understanding the immunological roles of pH sensing, which might reveal new strategies to combat inflammation and restore tissue homeostasis.

Highlights

• pH is a homeostatic variable tightly regulated at the cellular, tissue, and systemic levels. In particular, the regulation of tissue pH and the responses to pH perturvation remain poorly understood.

• Mammalian immune cells may be ideal sensors for tissue pH mediating both homeostatic and inflammatory responses.

• pH can be sensed by extracellular and intracellular receptors. Recent findings illustrate the crucial roles of extracellular receptors on immune cells, but the immunological functions of many pH sensing receptors remain to be uncovered.

• Responses to pH can be classified into two categories: effector functions that counter the pH deviation as negative feedback, and noneffector functions that facilitate adaptation to altered pH environments. Dysregulated pH detection, effector, and noneffector functions all create vulnerability for pathological outcomes.

• Understanding the immune mechanisms of pH-dependent response might spur the development and discovery of new therapeutic approaches in cancer and inflammatory disorders.

Link | Paywall (Trends in Immunology)