Inflammasome-gasdermin axis in bullous pemphigoid

大疱性类天疱疮的炎症小体-gasdermin轴

• 批准号: 10382402
• 负责人: Zhi Liu
• 金额: $ 37.38万
• 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/10382402
• 关键词: Antibodies; Autoantibodies; Autoimmune; Autoimmunity; Biological Models; Biology; Bone Marrow Transplantation; Bulla; Bullous Pemphigoid; CASP1 gene; Caspase; Cell membrane; Cellular Stress; Complement; Cytosol; Data; Disease; Extracellular Domain; Genes; Goals; Grant; IgG autoantibodies; Immune; 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; pathogenic autoantibodies; 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.

项目概要 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水疱性疾病 BP 自身抗体识别两种半桥粒蛋白 BP180 和 BP230。 抗 BP180 IgG 自身抗体可修复补体并具有致病性，NC16A 是 BP180 的胞外结构域。 是致病性自身抗体升高的促炎细胞因子 TNF-α 和 IL-1β 的主要靶标。 存在于 BP 患者的水疱液和血清中，然而，这些关键炎症介质的作用和作用。 我们的初步结果表明，它们如何在 BP 中上调仍不清楚。 致病性抗体诱导的形成依赖于 IL-1β，这是一种其分泌独特的细胞因子 我们进一步证明了特定的炎症体突变体。 小鼠抵抗 BP 的病理学因此，本提案的目的是研究 BP 的作用。 使用我们的 BP 小鼠模型研究 BP 中的炎症小体。我们对此提议的中心假设是 BP。 抗体触发炎症小体级联反应，从 NLRP3 炎症小体（目标 1）开始，激活 caspase-1 和 caspase-14（目标 3），最终激活gasdermin A，从而形成 IL-1β 分泌孔（目标 2）。该项目的总体目标是增加我们对先天免疫的了解。 BP 的作用及其与炎症和自身免疫中先天免疫系统参与者的功能的关系。 我们的初步数据很有希望，并且强烈支持我们的工作假设，因为该提案整合了。 无论是疾病机制还是临床前研究，这些发现预计将对 这笔补助金还将适用于治疗高血压和其他皮肤炎症性疾病。 对皮肤炎症基本生物学的影响 Gasdermin A 是一种已知的新先天免疫基因。 在细胞膜上形成孔，但其在体内的真正功能仍然是个谜，因为 IL-1β 是一种有效的物质。 和皮肤炎症疾病的中枢炎症介质，这些关于 Gasdermin A 的研究将有 广泛的影响并将揭示迄今为止难以想象的 IL-1β 分泌的基本生物学方面 角质形成细胞。

项目成果

Anti-NC16A IgA from Patients with Linear IgA Bullous Dermatosis Induce Neutrophil-Dependent Subepidermal Blistering in Mice.

来自线性 IgA 大疱性皮肤病患者的抗 NC16A IgA 会诱导小鼠中性粒细胞依赖性表皮下水疱。

• DOI: 10.1016/j.jid.2023.05.027
• 发表时间: 2024
• 期刊: The Journal of investigative dermatology
• 作者: Jing,Ke;Jordan,TylerJM;Li,Ning;Burette,Susan;Yang,Baoqi;Marinkovich,MPeter;Diaz,LuisA;Googe,Paul;Thomas,NancyE;Feng,Suying;Liu,Zhi
• 通讯作者: Liu,Zhi