Impact of CR on inflammasome driven immune-metabolic interactions.

描述（由申请人提供）：促炎细胞因子IL-1和IL-18的衰老诱导的增加与几种慢性疾病的发展相关。值得注意的是，我们的研究团队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增加依赖于称为Nlrp 3炎性体的多蛋白信号平台的组装。一种称为Nlrp 3炎性体的新型免疫传感器通过控制IL-1和IL-18的产生来控制骨髓细胞活化和炎症的几个方面。Nlrp 3（对于核苷酸结合结构域，富含亮氨酸重复序列的家族，含有pyrin结构域的-3）、衔接蛋白Asc和半胱天冬酶原1之间的蛋白质-蛋白质相互作用导致Nlrp 3炎性体的组装和半胱天冬酶-1的活化。半胱氨酸蛋白酶caspase-1是骨髓细胞分泌IL-1和IL-18所必需的。因此，抑制人类过度炎性小体激活的饮食干预与延迟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，将动物研究产生的结果转化为人类的实验室到床边的工作尤其具有挑战性，因为在特定无病原体设施中饲养的近交动物品系中的大多数CR研究不能模拟在整个寿命期内响应于病原体暴露的正常人类免疫细胞活化和失活。此外，人类Nlrp 3炎性小体组装所需的关键蛋白质如CARDINAL/CARD 8在小鼠中不存在。此外，炎性小体和半胱天冬酶-1的抑制性调节剂，如ICEBERG和印加，存在于人类中，但在蠕虫、苍蝇或小鼠模型中不存在。因此，除非在人类中研究特定的炎性小体调节机制，否则在动物模型中评估CR对炎症影响的研究是不完整的。CALERIE-II研究目前正在评价2年CR对人体生理学的影响。使用来自我们实验室中收集的对照和CR受试者的存档免疫细胞样品和来自CALERIE储存库的脂肪组织活检，我们提出测试以下假设：CR诱导的Nlrp 3炎性体激活失活打破了炎症的前馈回路并防止非肥胖成年人的代谢功能障碍。该项目将使我们能够评估关于CR与炎症之间关系的特定假设和预测，以及骨髓细胞在脂肪免疫串扰中的作用-特别是Nlrp 3炎症体激活的机制-对开发未来的饮食干预或促进人类健康的药理学治疗策略的影响。

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.