Inflammasome-gasdermin axis in bullous pemphigoid

大疱性类天疱疮的炎症小体-gasdermin轴

• 批准号: 9899921
• 负责人: Zhi Liu
• 金额: $ 38.99万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899921
• 关键词: Antibodies; Autoantibodies; Autoimmune Process; Autoimmunity; Biological Models; Biology; Bone Marrow Transplantation; Bulla; Bullous Pemphigoid; CASP1 gene; Caspase; Cell membrane; Cellular Stress; Cleaved cell; Complement; Cytosol; Data; Disease; Extracellular Domain; Genes; Goals; Grant; Immune; Immunoglobulin G; In Vitro; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Injections; Innate Immune System; Interleukin-1 beta; Knockout Mice; Liquid substance; Mediating; Molecular; Mus; Mutant Strains Mice; Natural Immunity; Neutrophil Infiltration; Neutrophilic Infiltrate; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Positioning Attribute; Proteins; Research; Resistance; Role; Signal Pathway; Signal Transduction; Skin; Surveys; TNF gene; Testing; Therapeutic; caspase 14; cytokine; effective therapy; experimental study; in vivo; in vivo Model; innate immune function; keratinocyte; macrophage; mouse model; neutrophil; preclinical study; sensor; translational impact

Project Summary Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease characterized by autoantibodies and an inflammatory infiltrate. BP autoantibodies recognize two hemidesmosomal proteins, BP180 and BP230. Anti-BP180 IgG autoantibodies fix complement and are pathogenic. NC16A, an extracellular domain of BP180, is the primary target of pathogenic autoantibodies. Elevated proinflammatory cytokines TNF-α and IL-1β are present in blister fluids and sera of BP patients. However, the roles of these critical inflammatory mediators and how they are up-regulated in BP remain unknown. Our preliminary results showed that subepidermal blister formation induced by pathogenic antibodies is dependent on IL-1β, a cytokine whose secretion is uniquely dependent upon the inflammasome signaling pathway. We further show that specific inflammasome mutant mice resist the pathology of BP. Therefore, the objective of this proposal is to study the role of inflammasomes in BP using our BP mouse models. Our central hypothesis for this proposal is that BP antibodies trigger an inflammasome cascade starting with the NLRP3 inflammasome (Aim 1), that activates caspase-1 and caspase-14 (Aim 3), culminating in the activation of gasdermin A, which forms the IL-1β secretion pore (Aim 2). The overall goal of this project is to increase our understanding of the innate immunity of BP and how it relates to the functions of innate immune system players in inflammation and autoimmunity. Our preliminary data are promising and strongly support our working hypothesis. Since this proposal integrates both disease mechanistic and preclinical studies, the findings are expected to have a significant impact on the treatment of patients with BP and other skin inflammatory disorders. This grant will also have broader implications to the basic biology of inflammation in the skin. Gasdermin A is a new innate immune gene known to form a pore in the cell membrane, yet its true function in vivo remains a mystery. Because IL-1β is a potent and central inflammatory mediator in skin inflammatory disease, these studies with gasdermin A will have broad impact and will reveal hitherto unimagined aspects of the basic biology of IL-1β secretion from keratinocytes.

项目摘要 大疱性类天疱疮（BP）是一种以自身抗体为特征的自身免疫性表皮下起泡疾病 和炎症浸润BP自身抗体识别两种半桥粒蛋白，BP 180和BP 230。 抗BP 180 IgG自身抗体固定补体并且是致病的。NC 16 A，BP 180的胞外结构域， 是致病性自身抗体的主要靶点。升高的促炎细胞因子TNF-α和IL-1β是 存在于BP患者的水疱液和血清中。然而，这些关键的炎症介质和 它们在BP中是如何被上调仍不清楚。我们的初步结果表明，表皮下水疱 由致病性抗体诱导的形成依赖于IL-1β，IL-1 β是一种细胞因子， 依赖于炎症体信号通路。我们进一步表明，特定的炎性小体突变体， 小鼠抵抗BP的病理学。因此，本提案的目的是研究 使用我们的BP小鼠模型在BP中发现炎性小体。我们对这一提议的中心假设是， 抗体触发一个炎性体级联反应，从NLRP 3炎性体（Aim 1）开始， caspase-1和caspase-14（Aim 3），最终激活gasdermin A，形成IL-1β， 分泌孔（Aim 2）。该项目的总体目标是增加我们对先天免疫的了解 以及它如何与先天免疫系统参与者在炎症和自身免疫中的功能相关。 我们的初步数据是有希望的，并强烈支持我们的工作假设。由于这一建议将 无论是疾病机制还是临床前研究，这些发现都有望对 治疗BP和其他皮肤炎性疾病的患者。这项赠款也将有更广泛的 对皮肤炎症的基础生物学的影响。Gasdermin A是一种新的先天免疫基因， 在细胞膜上形成一个小孔，但它在体内的真正功能仍然是一个谜。因为IL-1β是一种有效的 和中枢炎症介质在皮肤炎症性疾病，这些研究与gasdermin A将 广泛的影响，并将揭示迄今无法想象的方面的基本生物学的IL-1β分泌， 角质形成细胞