Carbon Dioxide Sensing by Immune Cells Occurs through Carbonic Anhydrase 2-Dependent Changes in Intracellular pH

CO₂, the primary gaseous product of respiration, is a major physiologic gas, the biology of which is poorly understood. Elevated CO₂ is a feature of the microenvironment in multiple inflammatory diseases that suppresses immune cell activity. However, little is known about the CO₂-sensing mechanisms and downstream pathways involved. We found that elevated CO₂ correlates with reduced monocyte and macrophage migration in patients undergoing gastrointestinal surgery and that elevated CO₂ reduces migration in vitro. Mechanistically, CO₂ reduces autocrine inflammatory gene expression, thereby inhibiting macrophage activation in a manner dependent on decreased intracellular pH. Pharmacologic or genetic inhibition of carbonic anhydrases (CAs) uncouples a CO₂-elicited intracellular pH response and attenuates CO₂ sensitivity in immune cells. Conversely, CRISPR-driven upregulation of the isoenzyme CA2 confers CO₂ sensitivity in nonimmune cells. Of interest, we found that patients with chronic lung diseases associated with elevated systemic CO₂ (hypercapnia) display a greater risk of developing anastomotic leakage following gastrointestinal surgery, indicating impaired wound healing. Furthermore, low intraoperative pH levels in these patients correlate with reduced intestinal macrophage infiltration. In conclusion, CO₂ is an immunomodulatory gas sensed by immune cells through a CA2-coupled change in intracellular pH.