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

• 批准号: 10459502
• 负责人: Sun-Sang Joseph Sung
• 金额: $ 61.85万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 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/10459502
• 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; interest; kidney cell; kinase inhibitor; macrophage; mesangial cell; mortality; nephrotoxicity; novel; novel therapeutics; podocyte; prevent; receptor; reproductive; response; systemic autoimmune disease; therapeutically effective; translational potential

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。增生性肾小球肾炎 (GN) 患者通常会进展至晚期 肾病 (ESRD) 的各个阶段。 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。我们的 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 LN 的临床结果非常重要。三种GN型号 已成立。通过一项新技术，我们在慢性肾小球肾炎中发现了独特的 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 导致足细胞消失和肾功能衰竭。我们发布的初步数据显示 NLRP3 的激活 足细胞中的炎症小体。此外，NLRP3 激活发生在 Tfh 细胞亚群中，该亚群具有强效 来激活B细胞。除了抑制足细胞中 NLRP3 的激活外，MCC950（特定激酶） NLRP3 抑制剂抑制自身抗体的产生和生发中心 (GC) 的形成。我们建议询问 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 B6 背景下小鼠的发育、GC 形成、抗体产生。类似的实验将会进行 在 NZM2328 背景的小鼠中，添加了自动抗体产生的测定和开发 液化天然气；具体目标 2：确定足细胞删除 NLRP3 激活途径基因的影响 在没有自身抗体减少的情况下，严重蛋白尿和早期死亡的发展；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 LN 和自发性 LN。这些结果 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 治疗 LN 的方法。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 细胞激活和终末器官损伤中的作用。因此该提案具有重大意义 与我们对免疫反应和转化潜力的理解相关的基础科学。