Transcriptomic analysis of epidermal sheets 1 week after induced keratinocyte deletion of A20 (Tnfaip3) in adult mice

A20 (TNFAIP3) is genetically associated with both Psoriasis and Psoriatic Arthritis in humans. We find that induced deletion of A20 (Tnfaip3) in keratinocytes leads to fully penetrant psoriatic cutaneous inflammation and Psoriatic Arthritis-like joint disease in adult mice. To determine the early molecular pathways that trigger skin and joint inflammation, we performed transcriptomic profiling of epidermal gene expression 1 week following induced deletion of keratinocyte A20 in adult mice. Pathways analysis identified elevation of genes associated with MyD88-dependent and antiviral signaling following keratinocyte A20 deletion. Using compund mutants that prevent keratinocyte MyD88 signaling or antiviral signaling from Type I interferon receptors, we found that keratinocyte MyD88 signaling is required for development of psoriatic skin and joint inflammation following keratinocyte A20 deletion. These results identify unrestrained MyD88 signaling as a key mediator of psoriatic inflammation and psoriatic arthritis-like pathology caused by deletion of keratinocyte A20 in adult mice. RNASeq profiling of ear epidermal sheets derived from 8 week old A20F/F Krt5-CreERT2+ (A20KIKO) and A20F/F Krt5-CreERT2- (A20WT) mice (four distinct mice in each group) 1 week after first intraperitoneal tamoxifen injection.