Inflammasomes and the mechanism of thymic demise in aging

描述（由申请人提供）：美国有3960万65岁或以上的老年人，预计到2030年这一数字将增加到约7200万。老年人免疫功能下降是发病率、生活质量下降和死亡的主要原因。有趣的是，胸腺的衰老先于其他器官的衰老，是晚年出现的免疫警觉性低下的主要特征和前兆。随着年龄的增长，胸腺产生幼稚T细胞的能力减弱，这在衰老研究中仍然是一个令人困惑的现象，迄今为止，这是一种难以解决的临床疾病，导致老年人的免疫功能障碍。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”作用之间关系的具体假设和预测，特别是导致胸腺损伤的炎性体激活机制，这对理解临床相关的基本途径以增强老年人的免疫系统具有重要意义。目前的建议是基于我们的发现，通过Nlrp3炎性体依赖机制降低胸腺内caspase-1的激活，可以大大延缓胸腺的衰老7。Nlrp3（核苷酸结合结构域，富含亮氨酸的家族，含pyrin结构域-3）炎性体是通过Nlrp3、Asc和前caspase-1蛋白之间的蛋白-蛋白相互作用形成的。Nlrp3炎性小体感知微生物副产物以及损伤相关分子模式（DAMPs），并在组装时引起caspase-1激活，从而控制促炎细胞因子IL-1b和IL-18的分泌。我们发现神经酰胺（鞘氨醇与脂肪酸相连的脂质）在衰老的胸腺中增加，触发Nlrp3炎性体的激活。消融小鼠Nlrp3炎性体可保护胸腺免于死亡，提示延缓免疫衰老。基于我们的新发现，本提案的中心假设是，年龄相关的胸腺脂毒性通过典型的Nlrp3炎性小体依赖机制诱导“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生成。该项目的总体目标是确定胸腺消亡的基本机制，以便于未来的临床干预，以延缓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.