002 The role of HIF-1α in the pathogenesis of psoriasis

Using an induced network module analysis of the deregulated genes in bulk transcriptome dataset of murine IMQ model and human psoriasis, we have identified HIF-1α (Hypoxia-inducible factor 1 alpha) as a central hub that links numerous psoriasis signature genes (e.g. S100A8, S100A9, NOS2, VEGFA, RORC, SERPINB3, etc.). In addition, HIF-1α showed a significant positive correlation with key psoriasis-associated clinical attributes such as acanthosis, hyperkeratosis, spongiosis, neutrophil-infiltration, and capillary density. Immunohistochemical staining of human skin biopsies of psoriasis demonstrated nuclear HIF-1α localization and thus its active form only in the middle layers of the epidermis where hypoxia might be at the highest level, as well as in the dermal infiltrates. A similar observation was made for HIF-1α downstream genes such as HK1 and CA9. Spatial transcriptomics data from lesional human psoriatic skin also revealed upregulation of HIF-1α transcripts specifically within the spinous layer of the psoriatic epidermis. These observations led us to hypothesize that HIF-1α might mediate the epidermal and dermal crosstalk while driving the formation of chronic psoriasis plaques and establishing a systemic inflammation. In vitro, both Th1 and Th17 cytokines can induce HIF-1α expression at RNA and protein levels in primary human keratinocytes and 3D epidermal cultures under normoxic condition. CRISPR-mediated deletion of HIF-1α resulted in reduced expression of psoriasis-signature genes such as NOS2, VEGFA, and IL-23 in 3D cultures stimulated with a psoriatic cytokine cocktail of IL-17 and IL-22. Conversely, DMOG-mediated stabilization of HIF-1α resulted in significant induction of VEGFA, NOS2, IL-23, CXCL8, and TNF-α. Our findings suggest that HIF-1α may play an important role in the pathogenesis of psoriasis.