Inflammatory memory sensitizes skin epithelial stem cells to tissue damage

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. After acute inflammation, epithelial stem cells retain a memory that accelerates restoration of the skin barrier during subsequent tissue damage, and this enhancement is dependent on the AIM2 inflammasome and its downstream effectors. In the skin, epithelial stem cells form a barrier against environmental damage. Shruti Naik et al. now show that after acute inflammation, epithelial stem cells retain a memory that hastens barrier restoration during subsequent tissue damage. However, the increased sensitivity to further insults may also increase tissue damage and susceptibility to other disorders such as autoimmune diseases and cancer.