NLRP3 Inflammasome Activation, T Follicular Helper Cells and Autoimmunity

点击翻译按钮获取中文摘要

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.