Impact of CR on inflammasome driven immune-metabolic interactions.

描述（由申请人提供）：衰老诱导的促炎细胞因子IL-1和IL-18的增加与几种慢性疾病的发展有关。值得注意的是，我们的研究小组和其他独立实验室最近的研究表明，热量过量诱导的IL-1和IL-18的增加依赖于称为Nlrp3炎症小体的多蛋白信号平台的组装。一种名为Nlrp3炎性小体的新型免疫传感器通过控制IL-1和IL-18的产生来控制髓细胞活化和炎症的几个方面。Nlrp3（核苷酸结合结构域，富含亮氨酸重复序列的家族，pyrin结构域-3）、接头蛋白Asc和原aspase1之间的蛋白-蛋白相互作用导致Nlrp3炎症小体的组装和caspase-1的激活。半胱氨酸蛋白酶caspase-1是髓系细胞分泌IL-1和IL-18所必需的。因此，抑制人类过度炎症小体激活的饮食干预与延缓由炎症引起的与年龄相关的慢性疾病高度相关。在动物模型中，热量限制仍然是延长健康寿命和减少炎症的最有效策略之一。然而，在免疫细胞功能和炎症的背景下，将动物研究结果从实验室到临床的转化工作尤其具有挑战性，因为大多数在特定无病原体设施中饲养的近交动物菌株的CR研究并不能模拟正常的人类免疫细胞在整个生命周期中对病原体暴露的激活和失活反应。此外，人类Nlrp3炎性体组装所需的关键蛋白，如CARDINAL/CARD8，在小鼠中不存在。此外，炎症小体和caspase-1的抑制调节因子，如ICEBERG和INCA，在人类中存在，但在蠕虫、苍蝇或小鼠模型中不存在。因此，在动物模型中评估CR对炎症影响的研究是不完整的，除非在人类中研究特定的炎症小体调节机制。CALERIE-II研究目前正在评估2年CR对人体生理的影响。利用我们实验室收集的对照和CR受试者存档的免疫细胞样本以及CALERIE存储库中的脂肪组织活检，我们提出验证CR诱导的Nlrp3炎症小体激活失活打破炎症的前馈循环并防止非肥胖成年人代谢功能障碍的假设。该项目将使我们能够评估CR与炎症之间关系的具体假设和预测，以及骨髓细胞在脂肪-免疫串音中的作用，特别是Nlrp3炎性小体激活的机制，这对开发未来的饮食干预或促进人类健康的药物治疗策略具有重要意义。

DESCRIPTION (provided by applicant): Aging-induced increases in pro-inflammatory cytokines IL-1 and IL-18 are associated with the development of several chronic diseases. Notably, recent studies from our research team and other independent laboratories have shown that caloric excess-induced increases in IL-1 and IL-18 are dependent on assembly of a multiprotein signaling platform called the Nlrp3 inflammasome. A novel immune sensor called the Nlrp3 inflammasome controls several aspects of myeloid cell activation and inflammation by controlling the production of IL-1¿ and IL-18. The protein-protein interactions between Nlrp3 (for nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing-3), the adaptor protein Asc, and procaspase1 lead to the assembly of the Nlrp3 inflammasome and caspase-1 activation. The cysteine protease, caspase-1, is required for the secretion of IL-1¿ and IL-18 from myeloid-lineage cells. The dietary interventions that dampen excessive inflammasome activation in humans are therefore highly relevant for delaying age-related chronic diseases that stem from inflammation. Caloric restriction remains one of the most robust strategies to extend healthspan and reduce inflammation in animal models. However, bench-to-bedside translation efforts of findings generated from animal studies to humans have been especially challenging in the context of immune cell function and inflammation because the majority of CR studies in inbred animal strains reared in specific pathogen-free facilities do not mimic normal human immune cell activation and deactivation in response to pathogen exposure throughout the lifespan. In addition, key proteins like CARDINAL/CARD8, which are required for the Nlrp3 inflammasome assembly in humans, are absent in mice. Furthermore, inhibitory regulators of inflammasomes and caspase-1, such as ICEBERG and INCA, are present in humans but are absent in worm, fly, or mouse models. Therefore, studies in animal models that evaluate the impact of CR on inflammation are incomplete unless specific inflammasome regulatory mechanisms are studied in humans. The CALERIE-II study is currently evaluating the impact of 2 year CR on human physiology. Using archived immune cell samples from control and CR subjects collected in our lab and adipose tissue biopsies from CALERIE repository, we propose to test the hypothesis that CR-induced deactivation of Nlrp3 inflammasome activation breaks the feed-forward loop of inflammation and prevents metabolic dysfunction in non-obese adults. This project will allow us to assess specific hypotheses and predictions about the relationships between CR and inflammation and role of myeloid cells in adipose-immune crosstalk - in particular the mechanism of Nlrp3 Inflammasome activation - with implications for developing future dietary interventions or pharmacological therapeutic strategies that promote human healthspan.