Keratinocyte expression of A20/TNFAIP3 controls skin inflammation associated with atopic dermatitis and psoriasis.

Keratinocytes are key players in chronic inflammatory skin diseases. A20 regulates NF-κB-dependent expression of pro-inflammatory genes and cell death, but the impact of its expression in keratinocytes on systemic inflammation and skin disorders has not been determined. Comparative transcriptomic analysis of micro-dissected epidermis showed that A20 is downregulated in involved epidermis, but not in dermis, of psoriasis (Pso) and atopic dermatitis (AD) patients suggesting that loss of A20 expression in keratinocytes increases the vulnerability for Pso/AD induction. We have previously shown that epidermis-specific A20 knock-out mice (A20) develop mild epidermal hyperplasia, but no macroscopic skin inflammation. We now show that various cytokines and chemokines are upregulated in A20 mouse skin. A20 mice also display systemic pro-inflammatory changes, even in the absence of skin immune cell infiltration, and an exacerbated disease severity upon induction of experimental Pso, AD or skin barrier disruption. Keratinocytes showed increased pro-inflammatory gene expression in the absence of A20 in unstimulated and IL-17A-stimulated conditions, in part resulting from uncontrolled MyD88-dependent signaling. Our findings indicate that absence of A20 in keratinocytes leads to systemic inflammation at homeostatic conditions and is sufficient to exacerbate inflammatory skin disorders associated with different immune profiles by increasing cytokine and chemokine expression.