pH sensing at the intersection of tissue homeostasis and inflammation

Abstract

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.

Keywords: acidic environment; adaptation; inflammatory response; pH homeostasis; pH sensing; resistance.

Figure 1:. Examples of pH in mammalian health and disease.

Various tissues and organs in our body maintain a unique pH to support their physiological functions. Each tissue possesses distinct mechanisms for pH regulation, ensuring a balanced internal environment conducive to cellular activities. Dysregulation in pH homeostasis is associated with disease or pathology (red) specific for the illustrated tissue compartment. The acid mantle helps maintain the antimicrobial defense of the stratum corneum. Rosacea or acne is associated with an elevated pH in the skin. Blood pH is tightly regulated within a narrow range of 7.35–7.45. Acidosis in severe sepsis is around pH 7.1–7.35. The pancreatic fluid is basic with a of pH 7.6–8.8 to neutralize the gastric content released into the duodenum. Chronic pancreatitis can reduce pH to 7.2. In the brain, the cerebrospinal fluid bathing meningeal immune cells maintains a mild acidic pH ~ 7.3. During ischemic injury, the CSF becomes more acidified to pH 6.6. Stomach acids have a pH 1.5–3.5 to activate digestive enzymes, while hypochlorhydria (pH 3–5) leads to poor nutrient absorption. The lumen of the small intestine is slightly alkaline (pH 7–8.5) for nutrient absorption. The acidic pH in the vaginal tract helps prevents the growth of opportunistic pathogens. Higher vaginal pH increases the risk of vaginitis. Lymph node paracortical zones in mice maintain an acidic pH (6.3–7.1) to limit unwarranted T cell activation. Solid tumors exhibit acidic pH ranging between 5.6–7.0 due to increased metabolic activity and proton extrusion by cancer cells (see text and box 1 for references).

Figure 2.. Homeostatic and Inflammatory circuits and feedback control of environment sensing.

The homeostatic circuit comprises four major components: regulated variables, sensors, homeostatic signals, and effectors. Deviations in regulated variables (such as pH or oxygen) from a set-point can be monitored by homeostatic sensors and corrected by effectors through a feedback mechanism. In parallel, the inflammatory circuit is initiated by sensing an inflammatory trigger (such as molecular cues of an infection or injury) by the sensor cells (e.g., macrophages, dendritic cells, airway epithelial cells). Inflammatory signals produced from the sensor cells can act on various cell types within a target tissue, activating inflammatory cascades and modulating tissue physiology to eliminate the inflammatory triggers as negative feedback. As a consequence of inflammation, many environmental variables, including pH, oxygen, lactate are perturbed from homeostatic range. Sensing the deviation of critical tissue microenvironment variables can serve as tunable feedback to limit tissue damage.

Figure 3:. The control circuits of homeostatic pH at systemic, cellular, and tissue levels.

In particular, the respiratory and renal homeostatic circuits control systemic pH regulation. In the respiratory circuit, pH alterations are sensed by receptors and ion channels, such as the G-protein coupled receptor (GPR4) and Two-Pore Domain Potassium Channels (TASK2) within central chemoreceptors and carotid glomus cells, which activate a neuronal reflex driving the modulation in the rate of ventilation and oxygen/carbon dioxide concentrations. In the renal circuit, luminal pH is sensed by GPCRs and Insulin-related like receptors (IRRs), and the proton/lactate flux is regulated by transporters and ion channels, ultimately driving bicarbonate resorption or proton excretion. Diseases, intoxication, and other disorders can threaten this balance. Severe metabolic or respiratory disorders, characterized by chronic acidosis or alkalosis, can lead to deviation in the blood pH from the normal range where pH < 7.35 is defined as acidosis and pH > 7.45 is defined as alkalosis. Acid base disturbances can be categorized as respiratory alkalosis/acidosis and metabolic alkalosis/acidosis. MCT: monocarboxylate transporter; NHE: Sodium proton exchanger. (see text and Boxes 2 and 3 for references).

Figure 4.. Extracellular and intracellular pH sensors.

(A). For illustration purposes only, the bubble plot depicts the expression of extracellular and intracellular pH-sensing receptors in various immune populations in mice (RNA-sequencing (seq) data from GSE109125) [111]. Normalized counts of bulk RNA-seq were aggregated based on the major immune cell types in the Immgen database. The sub cell types that were combined into the indicated immune population include different stages of development, distinct populations, or different tissue of origins. The average expression, as well as the standardized variance of all sub-types (standard deviation / mean) were shown as the dot size, and the color spectrum in the bubble plot. High variation likely indicates a tissue-specific or sub-type specific expression pattern. (B). The activation range of pH sensing receptors (from A) on the spectrum of homeostatic to pathological pH is shown.

Figure 5.. The impact of acidic extracellular pH on immune responses.

The table summarizes pH-dependent modulation on various immune cell types. Cellular responses related to survival, differentiation, metabolism, cytokine signaling, migration, antigen presentation, cytotoxicity, and cell death are impacted by acidosis or lactic acidosis (pH<7) in a context- and cell-type dependent manner [,,,,,,,,,–130]. In many cases, the underlying molecular mechanisms remain to be defined.

Key Figure, Figure 6.. Model of resistance and adaptation responses to pH perturbations.

(A) In response to an infection, sensor cells (e.g., macrophages, dendritic cells) secrete inflammatory mediators (e.g., TNF, IL-1β and IL-6) leading to the recruitment of effector cells (e.g., neutrophils, monocytes) that directly eliminate the pathogen as the resistance arm. The pro-inflammatory cytokines can also modulate other tissue targets (e.g., endothelial cells) to enable the inflammatory state as the adaptation arm of the response. In a second example, low oxygen tension is sensed by transcription factor HIF-1a, which induces angiogenic factors and activates glycolytic metabolism. New blood vessels deliver oxygen to relieve hypoxia (resistance) and anerobic glycolysis supplies energy (adaptation). (B) pH alterations from physiological and inflammatory perturbation can be sensed to regulate effector and non-effector functions in immune cells. The effector responses resist reduction in pH, by either directly regulating pH or the initial trigger that causes pH deviation. In contrast, pH responses can carry non-effector functions that are permissive for cells to adapt to a new pH environment. (see main text for references).