Resistin regulates NLRP3 inflammasome in pulmonary hypertension

抵抗素调节肺动脉高压中的 NLRP3 炎性体

• 批准号: 10567914
• 负责人: Roger A Johns
• 金额: $ 70.15万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567914
• 关键词: Address; Agammaglobulinaemia tyrosine kinase; Automobile Driving; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocytes; Binding; Blood Vessels; Bone Marrow; CASP1 gene; Cells; Cessation of life; Chemotaxis; Chronic; Clinical; Data; Development; Disease; Exposure to; Goals; HMGB1 gene; Heart; Heart failure; Homologous Gene; Human; Hypertension; Hypoxia; IL18 gene; Immune response; Immunotherapeutic agent; In Vitro; Inflammasome; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Innate Immune Response; Interleukin-1 beta; Investigation; Lung; Macrophage; Mediating; Mediator; Modeling; Modification; Molecular; Mus; Myeloid Cells; Pathologic; Pathway interactions; Patients; Pattern; Phenotype; Phosphorylation; Polymers; Process; Production; Proliferating; Proteins; Pulmonary Hypertension; Receptor Signaling; Recombinants; Reporting; Rodent; Rodent Model; Role; Scleroderma; Serum; Severities; Severity of illness; Signal Transduction; Smooth Muscle Myocytes; Structure of parenchyma of lung; Time; Tyrosine; Vascular Smooth Muscle; Vascular remodeling; Work; adaptive immune response; adaptive immunity; cell injury; chemokine; cytokine; diagnostic biomarker; hemodynamics; hypoxia-induced pulmonary hypertension; in vivo; migration; mortality; novel; polymerization; pulmonary vascular cells; pulmonary vascular remodeling; resistin; response to injury; vascular inflammation

PROJECT SUMMARY Extensive work has implicated human resistin (Hresistin) and its rodent correlate resistin-like molecule (RELM)- α in inflammatory mechanisms of pulmonary hypertension (PH). Elevated levels of Hresistin in the lungs of idiopathic PAH and Scleroderma PH patients1,2 correlate with the disease severity of PH and predict mortality.3 Rodent models of PH show RELMα is critical to PH remodeling of the lung vasculature and right heart.3-7 We reported Bruton’s Tyrosine Kinase (BTK) as a binding partner of RELMα/Hresistin,8 and mediator of chemokine activities of RELMα/Hresistin in myeloid cells.1,8 We also reported that, Hresistin/RELMα initiates the inflammatory response to injury at PH onset, through activating damage-associated molecular pattern (DAMP) pathway high-mobility group box-1 (HMGB1).1,4,9 However, it is unclear how Hresistin/RELMα’s diverse inflammatory effects are integrated or how they amplify and sustain inflammation to induce vascular remodeling over time. The NLRP3 inflammasome was recently suggested to be central to the vascular inflammation in PH.10 It mediates the innate response to injury and is associated with the transition to adaptive immunity. Here, we intend to demonstrate the novel concept that Hresistin/RELMα is a critical regulator of the priming and activation stages of the NLRP3 inflammasome. Our preliminary data suggests the hypothesis that Hresistin/RELM ritical α is c to both NLRP3 priming (via HMGB1)11 and NLRP3 activation (via BTK) and production of IL-1β and IL-18 (via critical BTK12 phosphorylation of four specific NLRP3 tyrosine residues) in both macrophages and B cells, leading to pulmonary vascular remodeling and PH. It suggests a major and novel role for Hresistin/RELMα in engaging the NLRP3 inflammasome in the innate immune response to injury and to a sustaining adaptive immune response in the long-term remodeling associated with PH. We address this hypothesis in two aims: Aim 1: To dissect and prove the detailed mechanism of how Hresistin regulates NLRP3 inflammasome in inflammatory cells; Aim 2: To investigate the contribution of Hresistin- regulated inflammasome to vascular remodeling and PH.

项目概要 大量研究表明人类抵抗素 (Hresistin) 及其啮齿动物相关抵抗素样分子 (RELM) - 肺动脉高压（PH）炎症机制中的α。肺部 Hresistin 水平升高 特发性 PAH 和硬皮病 PH 患者1,2 与 PH 疾病严重程度相关并预测死亡率。3 PH 啮齿动物模型显示 RELMα 对于肺血管系统和右心 PH 重塑至关重要。3-7 据报道，布鲁顿酪氨酸激酶 (BTK) 是 RELMα/Hresistin 的结合伴侣，8 和趋化因子的介质 RELMα/Hresistin 在骨髓细胞中的活性。1,8 我们还报道，Hresistin/RELMα 启动 通过激活损伤相关分子模式 (DAMP)，在 PH 发作时对损伤产生炎症反应 途径高迁移率组框-1 (HMGB1).1,4,9 然而，目前尚不清楚 Hresistin/RELMα 的多样性如何 炎症效应是整合的，或者它们如何放大和维持炎症以诱导血管重塑 随着时间的推移。 最近认为 NLRP3 炎症小体是 PH.10 中血管炎症的核心，它介导 对损伤的先天反应，并与向适应性免疫的过渡有关。在这里，我们打算 证明了 Hresistin/RELMα 是启动和激活阶段的关键调节因子的新概念 NLRP3 炎症小体。我们的初步数据表明，Hresistin/RELM 至关重要的假设 α 是 c NLRP3 启动（通过 HMGB1）11 和 NLRP3 激活（通过 BTK）以及 IL-1β 和 IL-18 的产生 （通过四个特定 NLRP3 酪氨酸残基的关键 BTK12 磷酸化）巨噬细胞和 B 细胞中， 导致肺血管重塑和PH。它表明 Hresistin/RELMα 在 NLRP3 炎症小体参与对损伤和持续适应性的先天免疫反应 与 PH 相关的长期重塑中的免疫反应。 我们通过两个目标来解决这一假设： 目标 1：剖析并证明 Hresistin 的详细机制 调节炎症细胞中的 NLRP3 炎症小体；目标 2：调查 Hresistin- 的贡献 调节炎症小体对血管重塑和 PH 的影响。