Inflammasome-gasdermin axis in bullous pemphigoid

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水疱病。 和炎性浸润物。BP自身抗体识别两种半染色体蛋白，BP180和BP230。 抗BP180自身抗体可固定补体并具有致病性。NC16A，BP180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肿瘤坏死因子-α和IL-1β是 存在于BP患者的疱液和血清中。然而，这些关键的炎症介质和 它们在英国石油公司是如何上调的仍是个未知数。我们的初步结果显示，真皮下水泡 致病抗体诱导的形成依赖于IL-1β，这是一种分泌独特的细胞因子 依赖于炎症体信号通路。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。因此，这项建议的目的是研究 使用我们的BP小鼠模型研究BP中的炎症体。我们对这一提议的中心假设是，英国石油公司 抗体触发从NLRP3炎症体(AIM 1)开始的炎症体级联反应，从而激活 Caspase-1和Caspase-14(目标3)，最终激活Gasdermin A，形成IL-1β 分泌孔(目标2)。这个项目的总体目标是增加我们对先天免疫的了解。 以及它与先天免疫系统成员在炎症和自身免疫中的作用有何关系。 我们的初步数据是有希望的，并有力地支持了我们的工作假设。由于本提案整合了 无论是疾病机制研究还是临床前研究，这些发现都有望对 治疗BP等皮肤炎性疾病。这笔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是已知的一种新的先天免疫基因 在细胞膜上形成一个孔，但它在体内的真正功能仍然是个谜。因为IL-1β是一种强大的 和中枢炎症介质在皮肤炎性疾病中的作用，这些关于加斯德明A的研究将会有 广泛的影响，并将揭示迄今无法想象的IL-1β分泌的基本生物学方面 角质形成细胞。

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.