Inflammasomes and Gasdermins in the Pathogenesis of Bullous Pemphigoid

大疱性类天疱疮发病机制中的炎症小体和 Gasdermin

基本信息

批准号：
10090561
负责人：
Stephen Kovacs
金额：
$ 5.1万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-24 至 2022-01-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10090561
关键词：
Adrenal Cortex Hormones Affect Antibodies Apoptotic Atopic Dermatitis Autoantibodies Autoimmune Diseases Automobile Driving Basement membrane Basic Science Binding Bone Marrow Transplantation Bulla Bullous Pemphigoid CASP1 gene CASP3 gene Cell Death Cell membrane Cells Characteristics Clinical Skills Complement Complement Membrane Attack Complex Cytolysis Data Dermis Development Diagnosis Disease Elderly Epidermis Europe Face Family Foundations Future Genes Goals Grant Hemidesmosomes Immune Immunology In Vitro Infection Inflammasome Inflammation Inflammation Mediators Inflammatory Knock-out Knockout Mice Knowledge Learning Liquid substance Lytic Maps Mediating Mediator of activation protein Membrane Modeling Mus Natural Immunity Neutrophil Infiltration Participant Passive Transfer of Immunity Pathogenesis Pathogenicity Pathology Pathway interactions Patients Peptide Hydrolases Physicians Protein Family Proteins Psoriasis Radiation Tolerance Recurrence Relapse Research Resistance Role Scientist Skin System Therapeutic Training United States career caspase 14 cell type cytokine effective therapy improved in vivo in vivo Model insight keratinocyte medical schools member mouse model neutrophil new therapeutic target novel novel therapeutics prevent protein activation protein complex radioresistant reconstitution recruit skin disorder skin organogenesis therapeutic development

项目摘要

SUMMARY/ABSTRACT Bullous pemphigoid is an autoimmune disorder characterized by the emergence of large, fluid-filled blisters on the skin of affected patients. It is caused by pathogenic antibodies that target BP180, a component of the hemidesmosomes that attach basal keratinocytes to the basement membrane of the epidermis. The antibodies promote inflammation and neutrophil recruitment, leading to the destruction of hemidesmosomes and separation of the epidermis from the dermis. Bullous pemphigoid is the most common blistering autoimmune disorder of the skin, and 10.8% of patients in the United States die within one year of diagnosis. Even in patients successfully treated for bullous pemphigoid, recurrence is common. Thus, novel therapeutics to better treat and prevent recurrence of bullous pemphigoid are needed. Our preliminary data shows that the NLRP3 inflammasome pathway and its end product, the inflammatory cytokine IL-1b, are required for neutrophil recruitment and blister formation in a well-established mouse model of bullous pemphigoid. Similarly, we observed that mice deficient in the keratinocyte-specific protein gasdermin A had significantly lower levels of IL-1b within the skin and were resistant to blister formation. Gasdermin A is a member of a family of proteins that includes gasdermin D, which was recently shown to mediate IL-1b release and lytic cell death downstream of inflammasome activation in immune cells. Therefore, we hypothesize that gasdermin A similarly acts downstream of inflammasome activation within keratinocytes to promote inflammation of the skin and bullous pemphigoid pathology. In AIM 1, we will determine in which cell types the NLRP3 inflammasome is activated in the mouse model of bullous pemphigoid using bone marrow transplants and cell type-specific IL-1b knockouts, and we will assess the role of terminal components of complement in activating NLRP3 using mice deficient in membrane attack pore formation. In AIM 2, we will compare the role and activation mechanism of gasdermin A and gasdermin D in the mouse model of bullous pemphigoid using mice deficient in gasdermin A and gasdermin D in the in vivo model of bullous pemphigoid, and by reconstituting gasdermin activation pathways in vitro. This grant is significant because it will provide foundational knowledge that may aid in the development of novel therapeutics that target inflammasomes and gasdermins to treat bullous pemphigoid. Furthermore, this grant will more broadly provide insights into the functions of keratinocytes as active participants of innate immunity and gasdermins as mediators of inflammation in the skin. Notably, to our knowledge, this would be the first in-depth characterization of gasdermin A as a mediator of skin inflammation. Thus, insights gained from this grant may improve our understanding of the pathogenesis of bullous pemphigoid and other inflammatory conditions of the skin as well as our understanding of how the skin protects against infection.

摘要/摘要大胆的幽灵是一种自身免疫性疾病，其特征是大型，充满液体的出现受影响患者的皮肤水泡。它是由靶向BP180的致病抗体引起的在表皮的基底膜上附着基底核细胞的半底体。这抗体促进炎症和嗜中性粒细胞募集，导致半idesm体的破坏表皮与真皮的分离。大笑的幽灵是最常见的起泡皮肤自身免疫性疾病，美国的患者中有10.8％在诊断后一年内死亡。即使在成功挑战大胆的雌雄同体的患者中，复发也很常见。那是新颖的治疗学为了更好地治疗和预防大胆的雌雄同体复发。我们的初步数据表明，NLRP3炎性途径及其最终产品，炎性细胞因子IL-1B是嗜中性粒细胞募集和泡沫形成所必需的小鼠大胆的小鼠模型。同样，我们观察到小鼠缺乏kerine-inopyte特异性的小鼠蛋白质加油机A在皮肤内具有明显较低的IL-1B水平，并且对水泡具有抗性形成。 Gasdermin A是包括Gasdermin D在内的蛋白质家族的成员，最近是证明可以介导免疫细胞中炎症体激活下游的IL-1B释放和裂解细胞死亡。因此，我们假设Gasdermin类似地作用于炎症体激活的下游角质形成细胞以促进皮肤炎症和大胆的雌性病理学。在AIM 1中，我们将确定在哪种细胞类型中nlrp3炎症体在鼠标中激活使用骨髓移植和细胞类型特异性IL-1B敲除骨的大肠刺激性模型，我们将评估完成终端组件在使用膜中缺乏小鼠激活NLRP3中的作用攻击孔形式。在AIM 2中，我们将比较Gasdermin a的角色和激活机制和使用缺乏加油动物A和Gasdermin d的小鼠的小鼠小鼠小鼠模型中的加油动物D 在大肠刺激性的体内模型中，并通过重新构成体外加油机激活途径。这项赠款很重要，因为它将提供可能有助于发展的基本知识靶向炎性症和加油动物的新型治疗剂可治疗大胆的芽孢杆菌。此外，这笔赠款将更广泛地提供有关角质形成细胞功能的见解，作为先天的活跃参与者免疫力和加油动物作为皮肤炎症的介体。值得注意的是，据我们所知，这将是 Gasdermin A作为皮肤炎症的介体的第一个深入表征。那是洞察力获得的从这笔赠款中可以提高我们对大胆的幽灵和其他的发病机理的理解皮肤的炎症条件以及我们对皮肤如何防止感染的理解。