P2X3 is a Female-Dominant Activator of Mast Cells

Abstract

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. Women are 60% more likely to be diagnosed with asthma and three times more likely to be hospitalized for it. In a search for possible new and upcoming drugs that might be repurposed to suppress mast cell function, we discovered that the ATP receptor P2X3, most often studied in neuropathic pain, has a role in mast cell activation. The P2X3 antagonist BLU-5937 suppressed IL-33 mediated-mast cell cytokine secretion in vitro and reduced neutrophilic peritonitis in vivo in female mice. In contrast, male mice and mast cells cultured from them showed no suppression when treated with BLU-5937. In addition, female mast cell responses were much stronger than males when activated with IL-33 in vitro. We also found that IL-33 elicits rapid ATP secretion by mast cells, possibly forming an autocrine loop via P2X3. These data coincided with little detectable P2X3 expression on male mast cells. We hypothesize that IL-33-mediated mast cell activation is more potent in females due to P2X3 receptor signaling. Our data support the theory that P2X3 is a female-dominant mast cell activator that can be targeted to reduce allergic inflammation. This research is novel because it could explain the sexual dimorphism in allergic disease and elucidate the role of P2X3 in the immune system. Supported by 1RO1 AI164710