Psoriasis and atopic dermatitis are inflammatory skin diseases driven by abnormal interactions between the immune system and epidermal keratinocytes. Therapeutic approaches have focussed on neutralising IL17A/TNFα or IL4, the dominant cytokines driving inflammation in psoriasis and atopic dermatitis, respectively. Whilst effective, only a small subset of patients receive these treatments due to the high cost and difficulty of administration, leaving an unmet need for additional therapies for the majority of patients with mild to moderate disease. To study the epidermal contribution to these diseases and identify potential therapies, we have performed FACS-based genome-wide CRISPR knockout screens in an immortalised human cell line to identify genes that regulate the keratinocyte response to IL17A/TNFα and IL4 treatment. This approach has identified positive and negative regulators of each cytokine pathway, including cytokine-specific targets and a number of hits that overlap with disease-specific GWAS identified variants. Using network analysis, we have identified several genetic subnetworks that commonly influence keratinocyte cytokine responses. We are currently validating these subnetworks in primary human epidermal keratinocytes using pharmacological and CRISPR-based approaches. We have also extended this experimental approach to study epidermal differentiation, a process impacted in both inflammatory skin disease and cancer.
