Inflammasomes and the mechanism of thymic demise in aging

描述（由申请人提供）：美国有3960万65岁或以上的人，预计到2030年将增加到约7200万。老年人免疫功能下降是发病、生活质量下降和死亡的主要原因。有趣的是，胸腺的老化先于其他器官的老化，并且是在以后的生活中出现的弱免疫警惕的中心特征和前兆。随着年龄的增长，胸腺产生幼稚T细胞的能力下降，这仍然是衰老研究中一个令人困惑的现象，迄今为止，这是一种导致老年人免疫功能障碍的棘手临床状况。该项目将使我们能够评估与年龄相关的胸腺死亡和“胸腺炎症”的作用之间的关系的具体假设和预测-特别是，导致胸腺损伤的炎性小体激活机制-与理解临床相关的基本途径，以加强老年人的免疫系统。目前的建议是基于我们的发现，即通过Nlrp 3炎性小体依赖性机制7降低胸腺内半胱天冬酶-1活化，可以显著延迟胸腺的衰老。Nlrp 3（nucleotide-binding domain，leucine-rich-containing family，pyrin domain-containing-3）炎性小体是通过Nlrp 3、Asc和caspase-1前体蛋白之间的蛋白质-蛋白质相互作用形成的。Nlrp 3炎性体感测微生物副产物以及损伤相关分子模式（DAMP），并且在组装时引起胱天蛋白酶-1活化，这反过来控制促炎细胞因子IL-1b和IL-18的分泌。我们确定了神经酰胺（具有与脂肪酸连接的鞘氨醇的脂质）在老化胸腺中增加，触发Nlrp 3炎性体的激活。小鼠中Nlrp 3炎性小体的消融保护胸腺免于死亡，表明延迟的免疫老化。基于我们的新发现，该提议的中心假设是，年龄相关的胸腺脂毒性通过典型的Nlrp 3炎症体依赖性机制诱导“胸腺炎症”，并通过影响胸腺上皮细胞的完整性而损害胸腺淋巴细胞生成。本项目的总体目标是确定胸腺死亡的基本机制，这些机制适合于未来的临床干预，以延迟甚至逆转中老年人的胸腺退化。

DESCRIPTION (provided by applicant): There are 39.6 million individuals aged 65 years or older in the US, a number expected to increase to approximately 72 million by 2030. Reduced immune function in the elderly is a major cause of morbidity, lower quality of life and death. Intriguingly, aging of thymus precedes aging of other organs and is a central feature and precursor of weak immune vigilance that appears in later life. Diminished ability of the thymus to produce naive T cells with progressive aging remains a puzzling phenomenon in Aging Research and to date, an intractable clinical condition that contributes to immune dysfunction in the elderly. This project will allow us to assess specific hypotheses and predictions about the relationship between age-related thymic demise and the role of 'thymic inflammaging' - in particular, the mechanism of inflammosome activation that causes thymic damage - with implications for understanding clinically relevant basic pathways to strengthen the immune system in the elderly. The current proposal is based on our discovery that aging of thymus can be substantially delayed by lowering the intrathymic caspase-1 activation via an Nlrp3 inflammasome dependent mechanism 7. The Nlrp3 (for nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome is formed via protein-protein interactions between Nlrp3, Asc and pro-caspase-1 proteins. The Nlrp3 inflammasome senses microbial byproducts as well as damage-associated molecular patterns (DAMPs) and upon assembly, causes caspase-1 activation, which in turn controls the secretion of pro-inflammatory cytokines IL-1b and IL-18. We identified that ceramides (lipids with sphingosine linked to a fatty acid) which increase in aging thymus, trigger the activation of Nlrp3 inflammasome. Ablation of Nlrp3 inflammasome in mice protects from thymic demise suggesting delayed immunological aging. Based on our novel findings, the central hypothesis of this proposal is that age-related thymic lipotoxicity via a canonical Nlrp3 Inflammasome dependent mechanism induces 'thymic inflammaging' and compromises thymic lymphopoiesis by impacting the integrity of thymic epithelial cells. The overall goal of this project is to identify basic mechanism of thymic demise that are amenable for future clinical intervention to delay or even reverse thymic involution in middle-aged or elderly people.