Naik Shruti, Larsen Samantha B, Gomez Nicholas C, Alaverdyan Kirill, Sendoel Ataman, Yuan Shaopeng, Polak Lisa, Kulukian Anita, Chai Sophia, Fuchs Elaine
Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.
Nature. 2017 Oct 26;550(7677):475-480. doi: 10.1038/nature24271. Epub 2017 Oct 18.
The skin barrier is the body's first line of defence against environmental assaults, and is maintained by epithelial stem cells (EpSCs). Despite the vulnerability of EpSCs to inflammatory pressures, neither the primary response to inflammation nor its enduring consequences are well understood. Here we report a prolonged memory to acute inflammation that enables mouse EpSCs to hasten barrier restoration after subsequent tissue damage. This functional adaptation does not require skin-resident macrophages or T cells. Instead, EpSCs maintain chromosomal accessibility at key stress response genes that are activated by the primary stimulus. Upon a secondary challenge, genes governed by these domains are transcribed rapidly. Fuelling this memory is Aim2, which encodes an activator of the inflammasome. The absence of AIM2 or its downstream effectors, caspase-1 and interleukin-1β, erases the ability of EpSCs to recollect inflammation. Although EpSCs benefit from inflammatory tuning by heightening their responsiveness to subsequent stressors, this enhanced sensitivity probably increases their susceptibility to autoimmune and hyperproliferative disorders, including cancer.
皮肤屏障是人体抵御环境侵害的第一道防线，由上皮干细胞（EpSCs）维持。尽管EpSCs易受炎症压力影响，但对炎症的初始反应及其长期后果都尚未得到充分了解。在此，我们报告了对急性炎症的长期记忆，这种记忆使小鼠EpSCs能够在随后的组织损伤后加速屏障修复。这种功能适应不需要皮肤驻留巨噬细胞或T细胞。相反，EpSCs在由初级刺激激活的关键应激反应基因处维持染色体可及性。在二次刺激时，由这些区域调控的基因会迅速转录。为这种记忆提供动力的是Aim2，它编码一种炎性小体激活剂。缺乏AIM2或其下游效应物caspase-1和白细胞介素-1β会消除EpSCs回忆炎症的能力。尽管EpSCs通过提高对后续应激源的反应性从炎症调节中受益，但这种增强的敏感性可能会增加它们对自身免疫性和过度增殖性疾病（包括癌症）的易感性。
