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

CO, the primary gaseous product of respiration, is a major physiologic gas, the biology of which is poorly understood. Elevated CO is a feature of the microenvironment in multiple inflammatory diseases that suppresses immune cell activity. However, little is known about the CO-sensing mechanisms and downstream pathways involved. We found that elevated CO correlates with reduced monocyte and macrophage migration in patients undergoing gastrointestinal surgery and that elevated CO reduces migration in vitro. Mechanistically, CO 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 CO-elicited intracellular pH response and attenuates CO sensitivity in immune cells. Conversely, CRISPR-driven upregulation of the isoenzyme CA2 confers CO sensitivity in nonimmune cells. Of interest, we found that patients with chronic lung diseases associated with elevated systemic CO (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, CO is an immunomodulatory gas sensed by immune cells through a CA2-coupled change in intracellular pH.