Keratinocytes Counteract UVB-Induced Immunosuppression in Mice through HIF-1a Signaling

The transcription factor Hypoxia-Inducible Factor-1alpha (HIF-1a) regulates cellular metabolism under hypoxia but also immune responses and UVB-induced skin reactions. In keratinocytes, HIF-1a is an environmental sensor orchestrating the adaptation to environmental changes. Here, we investigated the role of HIF-1a in keratinocytes for skin reactions to acute and chronic UVB exposure in mice. The function of HIF-1a in keratinocytes under UVB exposure was analyzed in conditional keratinocyte-specific HIF-1a-KO (in short “cKO”) mice. cKO mice were hypersensitive to acute high-dose UVB irradiation compared to wildtype (WT), displaying increased cell death and delayed barrier repair. After chronic low-dose UVB treatment, cKO mice also had stronger epidermal damage but reduced infiltration of dermal macrophages and T helper cells compared to WT mice. Irradiated cKO mice revealed accumulation of regulatory lymphocytes in dorsal skin-draining lymph nodes compared to WT and unirradiated mice. This was reflected by augmented IL-10 release of lymph node cells and a weaker contact hypersensitivity reaction to DNFB in UVB-exposed cKO mice compared to WT and unirradiated controls. In summary, we found that keratinocyte-specific HIF-1a expression is crucial for adaptation to UVB exposure and inhibits the development of UVB-induced immunosuppression in mice. Therefore, HIF-1a signaling in keratinocytes could ameliorate photoaging-related skin disorders.