Impaired Epidermal to Dendritic T Cell Signaling Slows Wound Repair in Aged Skin

Abstract

SUMMARY Aged skin heals wounds poorly, increasing susceptibility to infections. Restoring homeostasis after wounding requires the coordinated actions of epidermal and immune cells. Here we find that both intrinsic defects and communication with immune cells are impaired in aged keratinocytes, diminishing their efficiency in restoring the skin barrier after wounding. At the wound-edge, aged keratinocytes display reduced proliferation and migration. They also exhibit a dampened ability to transcriptionally activate epithelial-immune crosstalk regulators, including a failure to properly activate/maintain dendritic epithelial T-cells (DETCs), which promote re-epithelialization following injury. Probing mechanism, we find that aged keratinocytes near the wound edge don’t efficiently up-regulate Skints or activate STAT3. Notably, when epidermal Stat3, Skints or DETCs are silenced in young skin, re-epithelialization following wounding is perturbed. These findings underscore epithelial-immune crosstalk perturbations in general, and Skints in particular, as critical mediators in the age-related decline in wound-repair.

Inflammatory memory sensitizes skin epithelial stem cells to tissue damage

“…Moreover, using an assay that specifically measures keratinocyte migration (Extended Data Fig. 2f), we found that keratinocyte outgrowth from ex vivo explants post-inflammation 13 was more robust than controls (Fig. 1g).…”

“…Following a full-thickness wound, re-epithelialization is mediated by sensitized epidermal EpSCs, which transiently express K17 13 . Inflammation-experienced skin displayed enhanced epidermal thickness and accelerated re-epithelialization, but showed similar proliferation rates (Fig.…”

Skin and Its Regenerative Powers: An Alliance between Stem Cells and Their Niche

“…Immunofluorescence analyses of back skin and intravital videomicroscopy of ear skin shows that the process begins at ~12 hr post wounding with migration rates being highest (~1.6 µm/day) at the wound edge by day 3 (Aragona et al, 2017; Keyes et al, 2016; Park et al, 2017). By contrast, in a fashion similar to that seen in closure of the embryonic epidermis over the eyelid (Heller et al, 2014), the proliferative response occurs in the region behind and only partially overlapping with the migrating epidermal front (Park et al, 2017).…”

Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection

“…Regarding expression of homing and adhesion molecules of tissue-resident memory T cells, the γδ T cells from LNs of d28 IL-1β -/-mice had substantially decreased expression of CCR4 and significant but subtle differences in expression of CD103 and CLA compared with that in naive IL-1β -/-mice (Supplemental Figure 7). Finally, it is unclear whether the TCR signaling in the γδ T cells was required for protection; however, the butyrophilin family members (e.g., Skint1, Skint3, or Skint9) have recently been implicated as TCR ligands or costimulatory molecules for DETCs, which express the same CDR3 aa sequence (59,60). There was a significant correlation between reads encoding for the top γδ CDR3 sequences and BTLN2 (but not SKINT1, SKINT3, or SKINT9) in the LNs of d28 IL-1β mice (Supplemental Figure 8), suggesting that Btnl2 might activate the protective γδ T cells in our model.…”