Background/Purpose: A20 (Tnfaip3) levels are reduced in psoriatic plaques and polymorphisms in the TNFAIP3 gene locus are associated with increased risk for both psoriasis and psoriatic arthritis. A20 is a ubiquitin binding and editing molecule that acts as a key negative regulator of inflammatory signaling. Our prior work using knock-in mice showed that non-enzymatic A20 binding to linear ubiquitin restricted psoriatic skin and joint disease. The earliest inflammatory changes in these mice surrounded the epidermis of the distal digits. Therefore, we aimed to determine if keratinocyte A20 was critical for restricting psoriatic skin and joint disease.

Methods: We generated mice with tamoxifen inducible conditional deletion of A20 in keratinocytes (A20^eKO mice) and performed detailed immunological and transcriptomic analysis of tissues and primary keratinocytes in adult mice. We also generated multiple compound mutant mice with cytokines known to play a role in psoriatic arthritis.

Results: A20^eKO mice developed progressive psoriatic skin and joint disease of their distal digits with complete penetrance. Skin and joint pathology was dependent on TNF, IL17A, IL23, and T-cells, reflecting factors known to play a role in human psoriatic disease. The earliest in vivo transcriptomic changes following A20 deletion in keratinocytes demonstrated a profound antiviral gene program. Intriguingly, deletion of A20 in primary keratinocytes in vitro resulted in spontaneous activation of antiviral genes, dependent the presence of Sting (Tmem173).

Conclusion: A20 in keratinocytes restricts not only psoriatic skin disease, but also psoriatic joint disease, suggesting an important role for epidermal immune homeostasis in preventing arthritis. Skin and joint pathology is dependent on TNF, IL17A, IL23, and T-cells, demonstrating the importance of epidermal A20 in restricting psoriatic cytokine and cellular networks. Intriguingly, the earliest transcriptomic changes following epidermal A20 loss in vivo is an antiviral gene program. This is reflected by primary keratinocytes in culture, suggesting a cell autonomous role for A20 in restricting antiviral genes. Furthermore, spontaneous induction of antiviral genes in primary keratinocytes in vitro was Sting (Tmem173) dependent. Given the known presence of antiviral genes in human psoriatic plaques, these studies raise the possibility that A20 prevents psoriatic skin and joint pathology in part by restricting a Sting-dependent antiviral gene program in keratinocytes.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a20tnfaip3-in-keratinocytes-restricts-an-early-antiviral-gene-program-associated-with-psoriatic-skin-and-joint-disease/