PROJECT ABSTRACT Nearly a third of patients with psoriasis develop psoriatic arthritis; however, predicting which patients will develop arthritis remains challenging. Additionally, therapeutics are more successful in treating skin compared to joint disease. Clarifying the mechanisms which connect skin and joint disease in psoriasis may help identify patients at risk for arthritis earlier and may reveal novel therapeutic strategies. Polymorphisms in Tnfaip3 (A20), which reduce its expression, are associated with increased risk of both psoriasis and psoriatic arthritis. Furthermore, patients with psoriasis display reduced A20 levels compared to unaffected individuals. These data suggest that A20 is an important restrictor of psoriatic inflammation; however, the mechanisms by which A20 prevents psoriatic disease remain unknown. In our prior work, we generated a knock-in mouse mutant of A20 that developed spontaneous pathology analogous to psoriatic skin and joint disease. The earliest histological inflammation in these mice surrounded the epidermis, suggesting a role for keratinocytes. Therefore, we generated mice capable of inducible deletion of A20 in keratinocytes. Remarkably, these mice developed psoriatic skin and joint disease dependent on TNF, IL23, IL17A, and T-cells, reflecting known factors that mediate human psoriatic disease. To identify the earliest molecular events initiated by keratinocyte A20 loss, we performed RNASeq of epidermis one week after A20 deletion. Surprisingly, we found profound induction of antiviral genes. Antiviral genes are strongly expressed in human psoriatic plaques; however, the mechanism by which they are induced and their role in disease pathogenesis is unknown. Here we propose studies aimed at identifying the molecular mechanisms which activate antiviral gene programs following loss of keratinocyte A20. We will utilize in vitro culture systems of primary murine keratinocytes combined with strategies to inhibit specific interferon receptors and viral nucleic acid receptors. We will also determine whether the antiviral gene signature observed in vivo depends on the presence of cytokines known to play a role in psoriasis. Together, these studies may shed light on how antiviral genes are activated in human psoriasis and lead to an understanding of their pathogenic significance. As antiviral pathways are distinct from those currently targeted therapeutically, this may lead to novel treatment strategies and reveal new opportunities for pre-clinical biomarkers of psoriatic joint disease.