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年这一数字将增加到约7200万。老年人免疫功能低下是导致发病、生活质量下降和死亡的主要原因。耐人寻味的是，胸腺的衰老先于其他器官的衰老，这是免疫警戒性较弱的主要特征和先兆，这种免疫警觉性在以后的生活中出现。随着年龄的增长，胸腺产生幼稚T细胞的能力减弱，这在老龄研究中仍然是一个令人费解的现象，到目前为止，这是一种导致老年人免疫功能障碍的棘手的临床状况。这个项目将使我们能够评估与年龄相关的胸腺死亡与‘胸腺发炎’之间的关系的具体假设和预测--特别是导致胸腺损伤的炎症体激活的机制--这对理解临床上相关的增强老年人免疫系统的基本途径具有重要意义。目前的建议是基于我们的发现，通过降低胸腺内caspase-1的激活，通过Nlrp3依赖炎症体的机制7.Nlrp3(核苷酸结合域，富含亮氨酸的家族，含有吡咯结构域-3)炎症体是通过Nlrp3，Asc和caspase-1原蛋白之间的蛋白质-蛋白质相互作用而形成的。Nlrp3炎症体感知微生物副产物以及损伤相关的分子模式(DAMP)，在组装后导致caspase-1激活，进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(神经鞘氨醇与脂肪酸相连的脂类)在衰老的胸腺中增加，触发Nlrp3炎症体的激活。消融小鼠的Nlrp3炎性小体可以保护胸腺免于死亡，提示免疫衰老延迟。根据我们的新发现，这一建议的中心假设是，与年龄相关的胸腺脂肪毒性通过典型的Nlrp3炎症体依赖机制诱导‘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细胞的生成。本项目的总体目标是确定胸腺退化的基本机制，以便将来的临床干预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.