NLRP3 Inflammasome Activation, T Follicular Helper Cells and Autoimmunity

NLRP3 炎症小体激活、滤泡辅助 T 细胞和自身免疫

基本信息

批准号：
10250526
负责人：
Shu Man Fu
金额：
$ 61.85万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10250526
关键词：
Affect Age Alleles Antigen-Antibody Complex Attenuated Autoantibodies Autoantigens Autoimmune orchitis Autoimmunity B-Lymphocytes Basic Science Biological Assay CASP1 gene CD4 Positive T Lymphocytes Cell Compartmentation Cells Chronic Glomerulonephritis Clinical Collaborations Complex Control Locus Data Development Disease Disulfiram ENG gene Economics Effectiveness End stage renal failure FDA approved Female Flare Functional disorder Gene Deletion Gene Silencing Generations Genes Genetic Glomerulonephritis Glycogen (Starch) Synthase Helper-Inducer T-Lymphocyte Human ITGAM gene Immune Immune response Immunization Inflammasome Inflammation Inflammation Mediators Interferon-alpha Interleukin-1 beta Interleukin-18 Interleukin-6 Kidney Kidney Failure Laboratories Lead Lupus Lupus Nephritis Mediator of activation protein Modeling Mus Mutant Strains Mice Nephritis Organ Outcome Paper Pathogenesis Pathway interactions Patients Phosphotransferases Population Predisposition Production Proliferative Glomerulonephritis Proteinuria Publishing RIPK3 gene Reperfusion Injury Resistance Role Serum Structure of germinal center of lymph node Susceptibility Gene Systemic Lupus Erythematosus T-Cell Activation T-Cell Development TNF gene Techniques The Sun Therapeutic Tubular formation Universities Yang attenuation autoreactivity congenic cytokine effector T cell experimental study genomic locus inhibitor/antagonist interest kidney cell kinase inhibitor macrophage mesangial cell mortality nephrotoxicity novel novel therapeutics podocyte prevent receptor reproductive response systemic autoimmune disease therapeutically effective

项目摘要

Abstract Systemic lupus erythematosus (SLE) is a multi-organ systemic autoimmune disorder affecting mainly females in their reproductive ages. Patients with proliferative glomerulonephritis (GN) often progress to end stages of renal disease (ESRD). No new therapy for LN has been approved by the FDA for more than 50 years. A better understanding of the pathogenesis of LN is needed to devise more effective therapeutic strategies. Our laboratories have shown that immune complexes (IC) by themselves are not sufficient to cause ESRD, and end organ (kidney) resistance to damage is important in determining the clinical outcome of LN. Three GN models have been established. With a novel technique, we have identified in chronic glomerulonephritis that unique CD11b+IA-F4/80- infiltrating intraglomerular macrophages are the dominant cells that make TNFα, podocytes are the dominant cells that made IL-1β/IL-18 and mesangial cells make IL-6. A novel hypothesis is proposed that TNFα, IL-1β, IL-18 and IL-6 are made by different cells (compartments) in the diseased glomeruli and that the interactions among these cytokines with their receptors fuel the on-going inflammation within glomeruli leading to podocyte effacement and renal failure. Our published and preliminary data show activation of NLRP3 inflammasome in podocytes. In addition, NLRP3 activation occurs in a subpopulation of Tfh cells that are potent to activate B cells. In addition to the inhibition of NLRP3 activation in podocytes, MCC950, the specific kinase inhibitor of NLRP3 inhibits auto-Ab production and germinal center (GC) formation. We propose to interrogate the differential roles of NLRP3 activation in podocytes and Tfh cells in the pathogenesis of lupus GN. Three specific aims are proposed: Specific Aim 1: To utilize mutant mice with CD4 specific deletion of genes in the NLRP3 activation pathway to determine the effect of inactivation of these gene in CD4 T cells on Tfh cell development, GC formation, Ab-production in mice on B6 background. Similar experiments will be carried out in mice on NZM2328 background with the addition of assays for auto-Ab production and the development of LN; Specific Aim 2: To determine the effects of podocyte deletion of genes in the NLRP3 activation pathway on the development of severe proteinuria and early mortality in absence of auto-Ab reduction; Specific Aim 3: To demonstrate that lupus strains are intrinsically elevated in caspase-1 activated Tfh cells and hyper-responsive to immunization and Specific Aim 4: To interrogate the mechanism by which MCC950 inhibits NLRP3 activation, Tfh cell activation, GC formation and auto-Ab production and the attenuation of severe proteinuria in nephrotoxic serum (NTS) induced nephritis, IFN𝛼 accelerated LN and spontaneous LN. The results of these proposed experiments will provide convincing data to support targeting NLRP3 as an adjunct therapeutic approach in treating LN. They will provide definitive data regarding the roles of NLRPs activation and IL-1β and/or IL-18 in Tfh cell activation and end organ damage in autoimmunity. Thus the proposal has significance in basic science relating to our understanding of immunological responses and translational potentials.

抽象的系统性红斑狼疮（SLE）是一种多器官系统性自身免疫性疾病，主要影响处于育龄期的女性，患有增殖性肾小球肾炎 (GN) 的患者通常会进展至晚期。 50 多年来，FDA 尚未批准任何新的 LN 治疗方法。需要更好地了解 LN 的发病机制，以制定更有效的治疗策略。实验室已经表明，免疫复合物 (IC) 本身不足以引起 ESRD，并且结束器官（肾脏）对损伤的抵抗力对于确定三种 GN 模型的临床结果很重要。通过一项新技术，我们已经确定了慢性肾小球肾炎的独特之处。 CD11b+IA-F4/80-浸润肾小球内巨噬细胞是产生 TNFα、足细胞的主要细胞是产生 IL-1β/IL-18 的主要细胞，系膜细胞产生 IL-6。提出了一个新的假设。 TNFα、IL-1β、IL-18 和 IL-6 由患病肾小球中的不同细胞（区室）产生，并且这些细胞因子与其受体之间的相互作用加剧了肾小球内持续的炎症我们发表的初步数据显示 NLRP3 的激活。此外，NLRP3 激活发生在强效 Tfh 细胞亚群中。除了抑制足细胞中的 NLRP3 激活外，还可以激活 B 细胞，还可以抑制特定激酶 MCC950。 NLRP3 抑制剂抑制自身抗体的产生和生发中心 (GC) 的形成。足细胞和 Tfh 细胞中 NLRP3 激活在狼疮 GN 发病机制中的不同作用（三）提出了具体目标：具体目标 1：利用具有 CD4 特异性基因缺失的突变小鼠 NLRP3激活途径以确定CD4 T细胞中这些基因失活对Tfh细胞的影响将在 B6 背景下进行类似的实验。在 NZM2328 背景的小鼠中，添加了自动抗体产生的测定和开发 LN；具体目标 2：确定 NLRP3 激活途径中足细胞基因缺失的影响在没有减少自身抗体的情况下发生严重蛋白尿和早期死亡的具体目标 3：证明狼疮菌株在 caspase-1 激活的 Tfh 细胞和高反应性细胞中本质上升高免疫和具体目标 4：探究 MCC950 抑制 NLRP3 的机制激活、Tfh 细胞激活、GC 形成和自身抗体产生以及严重蛋白尿的减弱在肾毒性血清（NTS）诱发的肾炎中，IFN𝛼加速了LN和自发性LN的结果。拟议的实验将提供令人信服的数据来支持靶向 NLRP3 作为辅助治疗他们将提供有关 NLRP 激活和 IL-1β 作用的明确数据。和/或IL-18在自身免疫中Tfh细胞活化和终末器官损伤中的作用，因此该提议具有重要意义。与我们对免疫反应和转化潜力的理解相关的基础科学。