P2X3 Contributes to female-dominant IL-33 responses 2942

Abstract Description More than 300 million individuals suffer from asthma worldwide, and the severity of asthma and allergies has steadily increased over the last three decades. Asthma is a heterogeneous respiratory illness that damages bronchial epithelial cells, producing IL-33 and ATP. IL-33 and ATP are danger-associated molecular patterns (DAMPs) released in response to damage signals from injury, allergens, and microbes. Mast cells express receptors for both IL-33 and ATP. We find that IL-33-induced cytokine production is significantly higher in female-derived bone marrow mast cells (BMMCs) than in those derived from males. In addition, we observe that this sexual dimorphism is absent in mast cells lacking the ATP receptor, P2X3. In these BMMC populations, P2X3 knockout (KO) cells show reduced cytokine production selectively in females. IL-33 stimulation induces ATP release from mast cells, suggesting that P2X3 may participate in a positive feedback loop amplifying IL-33 function in females. In vivo experiments indicate that peritoneal mast cell numbers are reduced in P2X3 KO mice, and P2X3 deficiency selectively reduces IL-33-mediated eosinophilic peritonitis in females. These data support the hypothesis that an IL-33-ATP-P2X3 axis contributes to the sexual dimorphism observed in asthma and allergies. Funding Sources NIH/NIAID 1R01AI164710 Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)