Inflammatory memory sensitizes skin epithelial stem cells to tissue damage

Abstract

Summary 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.

Two to Tango: Dialog between Immunity and Stem Cells in Health and Disease

“…Given their burgeoning role in controlling stem cells, conversations between stem cells and tissue resident immune cells seem likely to become unhinged in disease states. This hypothesis is consistent with a number of pathological conditions are associated with loss of immune regulation, inflammation, and tissue hyperplasia (Gersemann et al, 2011; Lowes et al, 2007; Naik et al, 2017; Ordovas-Montanes et al, 2018a). …”

“…For instance, parasite infections result in the enrichment of Th2 cytokine IL-13, which signals to ISCs to drive differentiation of tuft and goblet cells that in turn, secrete mucus to aide in parasite expulsion and act to reinforce Th2 responses (Moltke et al, 2016). Moreover, during an active response, immune effectors localize to the vicinity of the stem cells to form the “inflamed niche” and instruct stem cell behavior (Biton et al, 2017; Naik et al, 2017). Accordingly, ISCs express receptors for a number of inflammatory mediators, enabling them to adjust to their specific inflammatory milieu (Biton et al, 2017; Lindemans et al, 2015; Moltke et al, 2016).…”

“…Unexpectedly, the link between inflammation, the inflammasome, IL-1β and epigenetic reprogramming of stem cells also has its reach outside the hematopoietic system, in this case, in the skin epithelial stem cells that experience an acute inflammation (Naik et al, 2017). While inflammatory memory has long been thought to be a phenomenon unique to hematopoietic lineages, surface epithelia bear the brunt of inflammation and ultimately are responsible for expeditious repair of tissue damage.…”

“…wounding, these experienced stem cells rapidly upregulate transcripts governed by accessible chromatin domains. A key mediator of this memory is the inflammasome activator AIM2, which augments IL-1β to promote the regenerative process following injury (Naik et al, 2017). …”

“…One area begging for insights is how epigenetic memory works, and how chromatin information can be propagated to offspring when stem cells divide. Inflammation-associated transcription factors such as STATs and NF-κB are activated rapidly by post-translational mechanisms, and the ensuing chromatin changes they elicit are notable in that they contain many accessible regions with sequence motifs not just for STATs and NF-κB but also for stem cell transcription factors (Naik et al, 2017). These newly accessible domains also contain binding sites for stem cell transcription factors, suggesting that they may remain open by binding these factors even when inflammation-activated TFs are no longer present.…”