Inflammatory memory sensitizes skin epithelial stem cells to tissue damage.
Inflammatory memory sensitizes skin epithelial stem cells to tissue damage.
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DOI：
10.1038/nature24271
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发表时间：
2017-10-26
期刊：
影响因子：
64.8
通讯作者：
Fuchs E
中科院分区：
文献类型：
--
作者：
Naik S;Larsen SB;Gomez NC;Alaverdyan K;Sendoel A;Yuan S;Polak L;Kulukian A;Chai S;Fuchs E
皮肤屏障是人体抵御环境攻击的第一道防线，由上皮干细胞(EpSCs)维持。尽管EPSC在炎症压力下很脆弱，但人们既不了解主要的反应，也不了解其持久的后果。在这里，我们发现了对急性炎症的长期记忆，使EPSCs能够在随后的组织损伤后加速屏障的恢复。这种功能适应不需要皮肤驻留的巨噬细胞或T细胞。相反，EPSCs在主要刺激激活的关键应激反应基因上保持染色体可及性。在第二次挑战中，由这些结构域控制的基因被快速转录。为这种记忆提供燃料的是AIM2，它编码了一种炎症体的激活剂。缺少AIM2或其下游效应物Caspase-1和IL-1β，会消除EPSCs回忆炎症的能力。虽然EPSC通过提高对后续应激源的反应性而受益于炎症调节，但这种增强的敏感性可能会增加它们对自身免疫和过度增殖疾病(包括癌症)的易感性。
The body’s first line of defense against environmental assaults, the skin barrier is maintained by epithelial stem cells (EpSCs). Despite EpSCs’ vulnerability to inflammatory pressures, neither the primary response nor its enduring consequences are understood. Here, we unearth a prolonged memory to acute inflammation that enables EpSCs to hasten barrier restoration following subsequent tissue damage. This functional adaptation does not require skin resident macrophages or T cells. Rather, 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. Fueling this memory is Aim2, encoding an activator of the inflammasome. Absence of AIM2 or its downstream effectors, Caspase-1 and Interleukin-1β, erases EpSCs’ ability to recollect inflammation. While EpSCs benefit from inflammatory tuning by heightening their responsiveness to subsequent stressors, this enhanced sensitivity likely increases their susceptibility to autoimmune and hyperproliferative disorders, including cancer.