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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：
9889794
负责人：
Stephen Kovacs
金额：
$ 4.42万
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/9889794
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/文摘