Abstract
Polymorphisms in the TNFAIP3 locus encoding the A20 protein are strongly associated with psoriatic skin and joint disease. Reduced A20 expression, driven by both genetic and epigenetic factors, underscores its critical role as a negative regulator of psoriatic disease (PsD). Our recent study using a germline knockin mouse model harboring a mutation in A20's seventh zinc finger, which impairs A20 binding to linear (M1) ubiquitin, revealed a spontaneous phenotype resembling psoriatic arthritis. These mice demonstrated sustained nuclear factor-κB signaling in response to transient tumor necrosis factor stimulation, leading to inappropriate transcription of mid- and late-response inflammatory genes. These findings highlight the role of dysregulated innate immune-signaling kinetics as a potential driver of PsD pathogenesis. These findings, together with distinct inflammatory mouse models resulting from temporally extended inflammatory gene activation, highlight the role of dysregulated innate immune-signaling kinetics as a potential driver of tissue inflammation with relevance to psoriatic skin and joint disease. This newly developed mouse model of PsD was presented at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2024 annual meeting.