Carbonic anhydrase 1 is a potent therapeutic target for mucosal and connective tissue mast cells 2261031

Abstract

Abstract Introduction Mast cells (MCs) are innate immune cells that play an important role in mediating allergic and inflammatory responses. MCs are derived from hematopoietic progenitor cells (HPCs) which migrate from the bone marrow to the periphery where they mature and reside. Mature mast cells are further classified as connective tissue mast cells (CTMC) and mucosal mast cells (MMC) based on their location, granule content and function. Upon activation, mature mast cells play important roles in promoting inflammatory diseases like allergic inflammation, mastocytosis, and autoimmune diseases via their release of diverse effector molecules. Despite the therapeutic need, a gap in understanding the factors that regulate mast cell development has limited our ability to design novel therapeutics to target mast cells. Our previous studies have identified a population of HPCs that possess mast cell potential and are defined by their expression of the metabolic enzyme carbonic anhydrase (Car)1. Here we show that genetically and pharmacologically targeting Car1 is sufficient to prevent the development of both CTMC and MMC in models of mastocytosis and atopic dermatitis-like diseases. Collectively, these studies demonstrate that Car1 is a viable therapeutic target for the treatment of pathologic CTMC as well as MMC and identify Car1 as a critical regulator of these distinct mast cell populations. Methods Genetically and pharmacologically targeting Car1 in both CTMC and MMC in models of mastocytosis and atopic dermatitis-like diseases. Results Here we show that genetically and pharmacologically targeting Car1 is sufficient to prevent the development of both CTMC and MMC in models of mastocytosis and atopic dermatitis-like diseases. Conclusion Collectively, these studies demonstrate that Car1 is a viable therapeutic target for the treatment of pathologic CTMC as well as MMC and identify Car1 as a critical regulator of these distinct mast cell populations. Funding Source n/a Topic Categories Translational and Interventional Immunology (TI)