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: 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
• 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

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）是一种多器官全身自身免疫性疾病，主要影响 女性在生殖时代。肾小球肾炎（GN）的增殖患者通常会发展为结束 肾脏疾病（ESRD）的阶段。 FDA批准了50多年的LN批准LN的新疗法。 需要更好地理解LN的发病机理，以设计更有效的治疗策略。我们的 实验室表明，免疫复合物（IC）本身不足以引起ESRD，并且结束 器官（肾脏）对损伤的抵抗对于确定LN的临床结果很重要。三个GN型号 已建立。通过一种新颖的技术，我们在慢性肾小球肾炎中鉴定出独特的 CD11b+IA-F4/80-浸润层状巨噬细胞是产生TNFα的主要细胞 是使IL-1β/IL-18和肾小球细胞产生IL-6的主要细胞。提出了一个新的假设 TNFα，IL-1β，IL-18和IL-6是由患病肾小球的不同细胞（隔室）制成的，并且 这些细胞因子与接收器之间的相互作用为glomerulli中持续的炎症加油 导致足细胞能量和肾衰竭。我们发布的初步数据显示了NLRP3的激活 足细胞中的炎性体。另外，NLRP3激活发生在有效的TFH细胞的亚群中 激活B细胞。除了抑制足细胞中NLRP3激活的MCC950，特异性激酶 NLRP3的抑制剂抑制自动生产和生发中心（GC）形成。我们建议讯问 NLRP3激活在足细胞和TFH细胞中的差异作用在狼疮GN的发病机理中。三 提出了具体目的：具体目的1：利用与CD4特异性缺失基因缺失的突变小鼠 NLRP3激活途径，以确定这些基因在CD4 T细胞中失活的影响 在B6背景下的小鼠中开发，GC形成，ab的生产。将进行类似的实验 在NZM2328背景的小鼠中，增加了自动生产的测定法和开发 ln;特定目的2：确定基因在NLRP3激活途径中的po核细胞缺失的影响 关于在没有自动AB降低的情况下，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细胞中本质上升高和超响应性 免疫和特定目的4：询问MCC950抑制NLRP3的机制 激活，TFH细胞激活，GC形成和自动AB产生以及严重蛋白尿症的衰减 在肾毒性血清（NTS）诱导的肾炎中，IFN𝛼加速LN和赞助LN。这些结果 拟议的实验将提供令人信服的数据，以支持针对NLRP3作为辅助疗法 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在自身免疫性中TFH细胞激活和最终器官损伤中。该提议具有重要意义 基础科学与我们对免疫反应和翻译潜力的理解有关。