Impact of CR on inflammasome driven immune-metabolic interactions.

描述(由申请人提供)：衰老引起的促炎细胞因子IL-1和IL-18的增加与几种慢性病的发展有关。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，卡路里过量诱导的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的新型免疫传感器通过控制IL-1和IL-18的产生来控制髓系细胞激活和炎症的几个方面。Nlrp3(核苷酸结合域、富含亮氨酸重复序列的家族、含派林结构域的-3)、适配蛋白Asc和Proaspase1之间的蛋白质-蛋白质相互作用导致Nlrp3炎症体的组装和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措施对于延缓源于炎症的与年龄相关的慢性疾病具有高度相关性。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力的策略之一。然而，在免疫细胞功能和炎症的背景下，将动物研究结果转换到床边的工作尤其具有挑战性，因为在特定的无病原体设施中饲养的近交系动物品系的大多数CR研究并不模拟正常的人类免疫细胞激活和失活，以应对整个生命周期中病原体的暴露。此外，人类Nlrp3炎症体组装所需的Cardinal/CARD8等关键蛋白在小鼠中缺失。此外，炎症小体和caspase-1的抑制调节因子，如冰山和印加，在人类中存在，但在蠕虫、苍蝇或老鼠模型中不存在。因此，在动物模型中评估CR对炎症的影响的研究是不完整的，除非在人类中研究特定的炎症体调节机制。CALERIE-II研究目前正在评估2年CR对人体生理学的影响。利用我们实验室收集的对照和CR受试者的存档免疫细胞样本和CALERIE储存库的脂肪组织活检，我们建议验证以下假设：CR诱导的Nlrp3炎症体激活失活打破了炎症的前馈循环，并防止了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和炎症之间的关系以及髓系细胞在脂肪免疫串扰中的作用的具体假设和预测--特别是Nlrp3感染小体激活的机制--这对开发未来促进人类健康的饮食干预或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.