P2X3 is a Female-Dominant Activator of Mast Cells

Abstract Asthma is characterized by increased mucus production, airway hyperresponsiveness and airway inflammation, all promoted by mast cell activation. There is a clear bias for greater incidence and acuity of asthma among females, but the reasons for this are not clear. In seeking FDA-approved drugs that might be repurposed to suppress mast cell function, we found that the selective serotonin reuptake inhibitor fluoxetine was able to suppress IgE mediated-mast cell degranulation and cytokine secretion in vitro, and protect against anaphylaxis in vivo. Fluoxetine effects appear to be mediated by an off-target interaction with the ATP receptor P2X3. Interestingly, male mice and mast cells cultured from them showed little fluoxetine responsiveness. These data coincided with little detectable P2X3 expression on male mast cells. Our data support the theory that P2X3 is a female-dominant mast cell activator that can be targeted with fluoxetine to reduce allergic inflammation. Female-biased P2X3 expression may also contribute to sexual dimorphism in allergic disease.