Impact of Ketone Metabolites on Inflammasome Deactivation in Gout

项目总结： 痛风是由尿酸盐晶体介导的激活引起的一种衰弱的炎症性疾病。 NLRP3炎症体。高脂饮食引起的衰老和代谢综合征 是痛风的主要危险因素。NALP3/NLRP3(针对NOD、LRR和PYRINE)的激活 结构域)被尿酸盐晶体诱导募集和自催化加工 半胱氨酸蛋白酶caspase-1在一个叫做‘炎症体’的大型胞浆蛋白复合体中。 Caspase-1的激活是裂解储存的IL-1前体β和 IL-18蛋白转化为具有生物活性的分泌细胞因子。炎性小体的聚集 需要ASC的吡咯域(PYD)的相互作用(对于凋亡相关的斑点样 含有羧基末端卡的蛋白质)与Nlrp3的PYD形成功能性 通过卡片-卡片的炎症体复合体(caspase激活招募结构域) 天冬氨酸氨基转移酶原-1酶原与ASC的相互作用因此，内生途径 而使炎症小体失活的代谢产物具有很高的临床影响。这 该建议是基于我们最近的发现，酮代谢产物β-羟基丁酸酯(BHb) 阻断NLRP3炎症体，调节先天免疫反应。酮 身体，BHB和乙酰乙酸酯(Acac)是支持 作为三氯乙酸中三磷酸腺苷来源的哺乳动物在饥饿期间的存活 当葡萄糖储备量低的时候循环。基于我们的原始发现和强大的科学性 前提1，这个项目的中心假设是生酮底物开关 是调节髓系反应的基础，它通过 炎性小体失活。推论是，升高BHB可能是一种 痛风的治疗。使用饮食和转基因方法来调节酮 身体新陈代谢，这项提议将测试BHB如何控制 巨噬细胞和中性粒细胞中的炎性小体激活。这样做的长期目标是 项目是开发酮类代谢物作为治疗痛风的药物。

PROJECT SUMMARY: Gout is a debilitating inflammatory disease caused by urate crystal mediated activation of the NLRP3 inflammasome. Aging and metabolic syndrome induced by high-fat diets are major risk factors for Gout. The activation of Nalp3/NLRP3 (for NOD, LRR and pyrin domain containing) by urate crystals induces recruitment and autocatalytic processing of cysteine protease caspase-1 in a large cytosolic protein complex called `inflammasome'. The activation of caspase-1, is required for the cleavage of stored pro-forms of IL-1β and IL-18 proteins into bioactive secreted cytokines. The assembly of inflammasomes requires interaction of pyrin domain (PYD) of ASC (for apoptosis-associated speck like protein containing carboxy terminal CARD) with PYD of Nlrp3 forming a functional inflammasome complex through CARD-CARD (caspase activation recruitment domain ) interaction of ASC with procaspase-1 zymogen. Therefore, the endogenous pathways and metabolites that deactivate the inflammasome have high clinical impact. This proposal is based on our recent findings that ketone metabolite β-hydroxybutyrate (BHB) blocks the NLRP3 inflammasome to regulate the innate immune response. The ketone bodies, BHB and acetoacetate (AcAc) are alternate metabolic fuels that support mammalian survival during periods of starvation by serving as a source of ATP in TCA cycle when glucose reserves are low. Based on our original findings and strong scientific premise1, the central hypothesis of this project is that ketogenic substrate switch underlies the regulatory myeloid responses that dampen metabolic inflammation via inflammasome deactivation. The corollary is that elevating BHB may serve as a treatment for Gout. Using both dietary and transgenic approaches that regulate ketone body metabolism, this proposal will test the mechanism of how BHB controls the inflammasome activation in macrophages and neutrophils. The long-term goal of this project is to develop ketone metabolites as therapeutics against Gout.