P2X3 is a Female-Dominant Amplifier of Mast Cell Function

P2X3 是肥大细胞功能的女性主导放大器

• 批准号: 10669711
• 负责人: John J Ryan
• 金额: $ 37万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669711
• 关键词: ATP Receptors; Allergic Disease; Allergic inflammation; Amplifiers; Antibodies; Antidepressive Agents; Asthma; B-Lymphocytes; Cell physiology; Cells; Cellular biology; Clinical; Complement; Data; Disease; Disparity; Estrogens; Extrinsic asthma; Female; Fluoxetine; Human; Hypersensitivity; IgE; In Vitro; Incidence; Intervention; Knockout Mice; MAP Kinase Gene; Mediating; Membrane; Modeling; Molecular; Mus; Natural Immunity; P2X-receptor; Pathology; Pathway interactions; Pharmaceutical Preparations; Production; Proteins; Public Health; Pyroglyphidae; Role; Sex Bias; Signal Induction; Signal Transduction; Testing; Therapeutic; Woman; allergic airway inflammation; autocrine; drug repurposing; eosinophil; in vivo; inhibitor; male; mast cell; novel; pain sensation; pain signal; patch clamp; receptor; release of sequestered calcium ion into cytoplasm; response; selective expression; sex; sexual dimorphism; translational progress

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.

项目概要 过敏性疾病发病率的上升是一项公共卫生挑战，需要新的干预措施。当桅杆 IgE 的细胞激活在疾病病理学中具有已知的作用，但肥大细胞生物学的基本方面仍然存在 不清楚。特别需要了解性别特异性的影响。雌性小鼠的肥大细胞具有 更强的 IgE 诱导反应，这一观察结果补充了过敏的更高发生率和严重程度 女性哮喘。为了重新利用药物，我们发现氟西汀（百忧解）可有效抑制 IgE 激活肥大细胞。这些数据在体外、体内以及与人类肥大细胞一致。然而， 氟西汀的作用明显仅限于女性。我们的结果表明氟西汀对 P2X3，一种 ATP 激活的阳离子通道，最常与疼痛信号传导相关。我们发现肥大细胞 响应 IgE 信号传导，快速释放 ATP，表明 P2X3 在自分泌循环中被触发。 P2X3 是 在女性肥大细胞上很容易检测到，但在男性肥大细胞上则不然，这可以解释为什么女性肥大细胞具有更强的 IgE 回应。与氟西汀一样，P2X3 选择性抑制剂极大地抑制肥大细胞对 IgE 或 ATP 的反应。 其他 P2X 蛋白的抑制剂没有效果。我们的研究将检验 IgE 信号传导引发 ATP 的假设 释放选择性激活女性体内的 P2X3，从而放大过敏性炎症。这条途径可以提供 过敏性疾病中性别二态性的解释和临床目标。 我们有三个具体目标： 目标 1：我们将检验 P2X3 增强女性肥大细胞功能的假设。 目标 2：我们将检验氟西汀通过抑制 P2X3 功能和表达发挥作用的假设。 目标 3：我们将检验以下假设：P2X3 是过敏性气道炎症的基本组成部分，可以通过 以女性为目标。