Unrestrained MyD88 Signaling in A20-Deficient Keratinocytes Triggers T-Cell-Dependent Psoriatic Arthritis-Like Disease.

Polymorphisms in A20 (TNFAIP3), a negative regulator of ubiquitin-mediated immune signaling, are strongly associated with psoriasis and psoriasis arthritis (PsA). The tissue-specific roles of A20 in preventing these diseases are poorly understood. Because cutaneous psoriasis typically precedes PsA by several years, skin inflammation may represent a key driver of joint disease. We now find that keratinocyte-specific deletion of A20 in normally developed adult mice spontaneously triggers both psoriasiform skin and joint disease, demonstrating a crucial role for epidermal A20 in restricting PsA-like pathology. Mice with A20-deficient keratinocytes that lack T cells were protected from PsA-like disease, showing a key role for epidermally triggered lymphocytes in driving joint inflammation. Early gene expression analysis after keratinocyte A20 deletion identified activation of MyD88 and antiviral signaling, reflecting spatial transcriptomic changes of human psoriatic epidermis. Keratinocyte-specific loss of A20 together with MyD88 but not germline disruption of IFN receptors in vivo protected mice from skin and joint pathology. A20-deficient primary keratinocytes from both mice and CRISPR-edited human cells spontaneously produced inflammatory cytokines and chemokines in vitro in a MyD88-dependent manner. A20-deficient murine keratinocytes also directly triggered IL-17A secretion from wild-type T cells. Together, our data demonstrate that keratinocyte A20 is critical for preventing T-cell-dependent PsA-like disease.