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: 10317599
• 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/10317599
• 关键词: ATP Receptors; Allergic Disease; Allergic inflammation; Amplifiers; Antibodies; Antidepressive Agents; Asthma; B-Lymphocytes; Cations; Cell physiology; Cells; Cellular biology; Clinical; Complement; Data; Disease; 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 Transduction; Testing; Therapeutic; Woman; allergic airway inflammation; autocrine; drug repurposing; eosinophil; in vivo; inhibitor/antagonist; male; mast cell; novel; pain sensation; pain signal; patch clamp; receptor; release of sequestered calcium ion into cytoplasm; response; selective expression; sex; sexual dimorphism

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.

项目摘要 过敏性疾病发病率的上升是一个公共卫生挑战，需要新的干预措施。虽然桅杆 已知IgE对细胞的激活作用在疾病病理学中起作用，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影响。雌性小鼠的肥大细胞 更强的IgE诱导的反应，补充了过敏反应的更大发生率和敏锐度的观察结果。 女性哮喘为了重新利用药物，我们发现氟西汀（百忧解）有效地抑制了 IgE激活肥大细胞。这些数据在体外、体内和人肥大细胞中是一致的。然而，在这方面， 氟西汀的作用明显局限于女性。我们的研究结果表明，氟西汀具有脱靶效应， P2X3是一种ATP激活的阳离子通道，通常与疼痛信号相关。我们发现肥大细胞 快速释放ATP响应IgE信号，表明P2X3在自分泌回路中被触发。P2X3是 在女性肥大细胞上容易检测到，但在男性肥大细胞上不能检测到，这可能解释了为什么女性肥大细胞具有更强的IgE 应答与氟西汀一样，P2X3选择性抑制剂极大地抑制了肥大细胞对IgE或ATP的反应。 其他P2X蛋白的抑制剂没有影响。我们的研究将验证IgE信号激发ATP的假设， 释放选择性激活女性P2 X3，加剧过敏性炎症。这条途径可以提供 变态反应性疾病中两性异形的解释和临床靶点。 我们有三个具体目标： 目的1：我们将测试P2X3增强女性肥大细胞功能的假设。 目的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。 目的3：我们将检验P2X3是过敏性气道炎症的基本部分这一假设， 针对女性。