Carbonic anhydrase 8 regulates basophil activation and interleukin 4 production

Jianya Peng^1,2,3Chandler B. Sy^2,4Siyuan Zhao⁵Arman Sawhney^2,6Vanessa Espinosa^6,7Marissa N. Schroeter^2,6,8John J. Ponessa^2,3,6Krupa Chavan^2,6Alexander D. Lemenze⁹Amariliz Rivera^6,7Tibor Rohacs⁵Mark C. Siracusa^2,3,4*

• ¹Center for Immunity and Inflammation, Rutgers, The State University of New Jersey, Newark, New Jersey, USA, United States
• ²Department of Medicine, Rutgers, The State University of New Jersey, Newark, New Jersey, United States
• ³NemaGen Discoveries, Princeton, New Jersey, United States
• ⁴Center for Immunity and Inflammation, Rutgers. The State University of New Jersey, Newark, United States
• ⁵Department of Pharmacology, Physiology, and Neuroscience, Rutgers, The State University of New Jersey, Newark, New Jersey, United States
• ⁶Center for Immunity and Inflammation, Rutgers, The State University of New Jersey, Newark, United States
• ⁷Department of Pediatrics, Rutgers, The State University of New Jersey, Newark, New Jersey, United States
• ⁸Department of Pharmacology, Physiology, and Neuroscience, Rutgers, The State University of New Jersey, Newark NJ, United States
• ⁹Department of Pathology, Immunology and Laboratory Medicine, Rutgers, The State University of New Jersey, Newark, New Jersey, United States

Carbonic anhydrase (Car) enzymes are a family of metalloenzymes that are traditionally known for their ability to regulate pH and CO2 homeostasis. However, emerging studies now demonstrate that Car family members exhibit lineage-specific expression patterns within immune cells. Moreover, it has been shown that genetically and pharmacologically targeting specific Car family members is sufficient to regulate immune cell development and activation. This work has identified Car enzymes as viable therapeutic targets that can influence immunity and inflammation. Here we contribute to this growing body of literature and demonstrate that Car8 is highly expressed by basophils and basophil precursor cells compared to other Car family members. While deletion of Car8 had no effect on basophil development or recruitment, mice deficient in Car8 were protected from basophil-and interleukin (IL)-4-dependent atopic dermatitis-like inflammation. Consistent with these findings, Car8-deficient basophils exhibit defects in the cytokine-stimulated release of IL-4 that is associated with altered calcium signaling pathways. Collectively, these studies reveal the lineage-specific expression patterns of Car8 and its unappreciated function in regulating basophil activation.