P2X3 is a Female-Dominant Amplifier of Mast Cell Function

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Project Summary The rising incidence of allergic disease is a public health challenge needing novel interventions. While mast cell activation by IgE has a known role in disease pathology, fundamental aspects of mast cell biology remain unclear. There is a particular need to understand sex-specific effects. Mast cells from female mice have stronger IgE-induced responses, an observation complementing the greater incidence and acuity of allergic asthma among women. In an effort to repurpose drugs, we found that fluoxetine (Prozac) potently suppresses mast cell activation by IgE. These data were consistent in vitro, in vivo, and with human mast cells. However, fluoxetine effects were strikingly female-restricted. Our results indicate fluoxetine has an off-target effect on P2X3, an ATP-activated cationic channel most often associated with pain signaling. We find that mast cells rapidly release ATP in response to IgE signaling, suggesting P2X3 is triggered in an autocrine loop. P2X3 was readily detectable on female but not male mast cells and may explain why female mast cells have stronger IgE responses. Like fluoxetine, P2X3-selective inhibitors greatly suppressed mast cell responses to IgE or ATP. Inhibitors of other P2X proteins had no effect. Our study will test the hypothesis that IgE signaling elicits ATP release that activates P2X3 selectively in females, amplifying allergic inflammation. This pathway could offer an explanation and a clinical target for sexual dimorphism in allergic disease. We have three Specific Aims: Aim 1: We will test the hypothesis that P2X3 enhances mast cell function in females. Aim 2: We will test the hypothesis that fluoxetine acts by suppressing P2X3 function and expression. Aim 3: We will test the hypothesis that P2X3 is a fundamental part of allergic airway inflammation that can be targeted in females.