Abstract: The skin serves as a primary defense by altering cellular behavior in response to infection or external stressors, which triggers an inflammatory response. While the immunological aspects of skin inflammation have been studied, the crosstalk between the stem cell niche and inflammatory signals remains poorly understood. Here, we utilize a mouse model of 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced acute skin inflammation to investigate how inflammation impacts epidermal stem cell heterogeneity and tissue remodeling. The topical application of TPA induces inflammation in mouse skin, as indicated by a significant increase in epidermal thickness, hyperproliferation, and elevated levels of pro-inflammatory cytokines. By lineage tracing, we demonstrate that Dlx1+ slow-cycling stem cell clones persist and exhibit high resistance to inflammation. In contrast, Slc1a3+ fast-cycling stem cell clones are progressively lost by differentiation, resulting in a reduction in epidermal compartment size in the skin. The decoy receptor IL-1R2, which is highly expressed in the slow-cycling stem cell compartment, suggests a potential link between the observed imbalance in epidermal stem cell heterogeneity and IL-1 signaling during inflammation. The intradermal injections of IL-1a or IL-1b induce similar stem cell alterations in stem cell populations as observed in the TPA model. Conversely, overexpression of IL-1R2 mitigates these changes, indicating a dependence on IL-1 signaling. Transcriptome analysis reveals that inflammatory signals may interfere with normal niche signaling, leading to an impairment of the epidermal stem cell heterogeneity during TPA-induced inflammation. These results provide new insights into the cellular dynamics of epidermal stem cells during skin inflammation and highlight IL-1 as a critical immune signaling that disrupts the heterogeneous epidermal stem cell populations under pathological tissue remodeling in inflammatory skin.
Funding Source: AMED, 24bm1123052, AMED-PRIME, AMED (21gm6110016), Grant-in-Aid for Scientific Research (B) (24K02035, 20H03266), The Sumitomo Foundation, Takeda Science Foundation, Naito Foundation, Koyanagi Foundation (all to A.S.), MEXT.
