The transcription factor Hypoxia-Inducible Factor-1alpha (HIF1a) regulates metabolic functions under hypoxia and is also involved in responses of the skin to UVB exposure as well as in immune responses. We found that HIF1a differentially modulated cytokine release of cultivated keratinocytes under hypoxia and upon UVB exposure. Further, conditional keratinocyte-specific HIF1a-KO mice (cHIF1aK5cre) were more susceptible to skin damage by acute high-dose UVB irradiation compared to WT controls. 
We aim to analyse the function of HIF1a in keratinocytes during in vivo subchronic low-dose UVB exposure and specifically study inflammatory pathways, adaptive changes of the skin and the development of UVB-induced immunosuppression. 
cHIF1aK5cre mice and control littermates were subjected to subchronic low-dose UVB irradiation and/ or underwent subsequent induction of contact hypersensitivity by DNFB to assess UVB-induced immunosuppression. 
After subchronic UVB treatment, cHIF1aK5cre mice showed increased transepidermal water loss and stronger epidermal damage compared to WT. Dermal infiltration of macrophages was detected in irradiated WT, but not cHIF1aK5cre mice. Flow cytometry of draining lymph nodes revealed an accumulation of regulatory T and B cells in cHIF1aK5cre mice compared to WT littermates and untreated controls. In line, contact hypersensitivity induction by DNFB proved a weaker ear swelling response upon challenge in UVB-exposed cHIF1aK5cre mice compared to WT and unirradiated controls. This demonstrates that loss of HIF1a signaling in keratinocytes facilitates UVB-induced immunosuppression in mice. 
In summary, we found that keratinocyte-specific HIF1a signaling is involved in adaptation to UVB exposure and notably inhibits the development UVB-induced immunosuppression. This underscores that keratinocytes significantly modulate photoaging-related skin disorders via HIF1a signaling.

Keratinocyte-Specific Function of Hypoxia-Inducible Factor-1alpha (HIF1a) in UVB-Induced Immunosuppression