Defining the role of NF-kB signaling as a key driver of pancreatic beta-cell aging and heterogeneity

胰岛是一个细胞群落，承载着产生胰岛素的β细胞，众所周知，它会经历与年龄相关的变化。特别是，衰老与β细胞更新能力的降低有关，而2型糖尿病是一种与年龄相关的疾病。然而，目前只发现了少数与衰老有关的信号。通过比较年轻和年长动物的β细胞，我的团队发现，老化的胰岛显示出慢性炎症的迹象。这些迹象包括募集表达细胞因子肿瘤坏死因子α的巨噬细胞和激活核因子-kB信号(一种信号通路，几乎在所有动物细胞类型和感觉炎症的组织中都存在)。有趣的是，核因子-kB的激活并不是均匀的，而是异质地分布在β细胞群体中，这意味着不同的β细胞表现出不同程度的炎症。那些在较高水平激活核因子-kB信号的β细胞也会过早上调一种抑制其增殖的基因。细胞复制优先地由逃避与年龄相关的核因子-kB信号激活的β细胞亚群维持。总之，这些结果证明了老年动物慢性胰岛炎症的发展，高水平的核因子-kB信号标志着随着年龄的增长而失去增殖能力的细胞。我们的研究发现，组织渗透的免疫细胞是与年龄相关的炎症的潜在来源。在这项提案中，我们计划了解免疫细胞释放的特定信号，这将有助于确定它们在调节胰岛炎症中的作用。此外，我们将测试药物和遗传的核因子-kB信号抑制(其成分的失活)是否可以使衰老的胰岛恢复活力，以增加β细胞的更新。最后，我们的一些新的初步数据表明，在特定条件下，高水平的核因子-kB信号赋予β细胞特殊的优势。我们正在探索这一未知的方面，因为这些知识可以帮助改进目前用于糖尿病治疗的胰岛分离和移植的策略。

The pancreas islet, a cellular community that hosts the insulin-producing beta cells, is known to undergo age-related changes. In particular, aging is associated with a reduction in the renewal capacity of beta-cells and type 2 diabetes is an age-related disease. However, only a handful of signals have been identified in connection with ageing. By comparing beta cells from younger and older animals, my group showed that the aging islets show signs of chronic inflammation. These signs include recruitment of macrophages that express the cytokine TNFα and the activation of NF-kB signaling (a signaling pathway found in virtually all animal cell types and tissues that senses inflammation). Interestingly, the activation of NF-kB is not uniform but heterogeneously distributed across the beta-cell population, meaning that different beta-cells exhibit different levels of inflammation. Those beta-cells that activate NF-kB signaling at higher levels also upregulate prematurely a gene that inhibits their proliferation. Cell replication is preferentially maintained by a subpopulation of beta-cells that escape the age-related activation of NF-kB signaling. Altogether, the results document the development of chronic islet inflammation in older animals, with high levels of NF-kB signaling marking the cells that lose proliferative potential with age.Our study identified tissue-infiltrating immune cells as a potential source of age-related inflammation. In this proposal, we plan to understand the specific signals that the immune cells release, which will help define their role in regulating islet inflammation. Furthermore, we will test whether pharmacological and genetic NF-kB signaling inhibition (inactivation of its components) can rejuvenate the aging islet in order to increase beta-cell renewal. Finally, some of our new preliminary data indicate that having high levels of NF-kB signaling confer a particular advantage to the beta-cells under specific conditions. We are exploring this unknown aspect because the knowledge could help improve current strategies for islet isolation and engraftment for diabetes-treatment.