Inflammatory Memory in Epidermal Stem Cells Accelerates Tissue Damage Responses

The body's first line of defense against environmental assaults, the skin's barrier, is maintained by epidermal stem cells (EpdSCs). Despite EpdSC's vulnerability to inflammatory pressures, neither their primary response nor its enduring consequences are understood. Here, we unearth a prolonged memory to acute inflammation that enables EpdSCs to hasten barrier restoration following subsequent tissue damage. This functional adaptation does not require resident skin T cells. Rather, EpdSCs maintain chromosomal accessibility at key regions activated by the primary stimulus. Upon secondary challenge, genes regulated by these domains are rapidly transcribed. Aim2, encoding an activator of the inflammasome, is at the crux of this memory as blocking the AIM2 effector Caspase-1 erases inflammation-exposed EpdSC's recollection. The inflammatory tuning of EpdSCs has significant therapeutic implications: while enabling EpdSCs to cope with recurrent stress by enhancing their barrier repair capabilities, it may also render them more susceptible to autoimmune and hyperproliferative disorders, including cancer. Overall design: mRNA (RNA-seq, 16 samples) and chromasomal accessibility (ATAC-seq, 8 samples) profiles from fluorescence-activated cell sorted (FACS) EpdSCs from adult normal, imiquimod inflamed, and wounded skin.