MALT1 targeting suppresses CARD14-induced psoriatic dermatitis in mice.

CARD14gain-of-function mutations cause psoriasis in humans and mice. Together withBCL10 and the proteaseMALT1, mutantCARD14 forms a signaling node that mediates increasedNF-kappa B signaling and proinflammatory gene expression in keratinocytes. However, it remains unclear whether psoriasis in response toCARD14 hyperactivation is keratinocyte-intrinsic or requiresCARD14 signaling in other cells. Moreover, thein vivoeffect ofMALT1 targeting on mutantCARD14-induced psoriasis has not yet been documented. Here, we show that inducible keratinocyte-specific expression ofCARD14(E138A)in mice rapidly induces epidermal thickening and inflammation as well as increased expression of several genes associated with psoriasis in humans. Keratinocyte-specificMALT1 deletion as well as oral treatment of mice with a specificMALT1 protease inhibitor strongly reduces psoriatic skin disease inCARD14(E138A)mice. Together, these data illustrate a keratinocyte-intrinsic causal role of enhancedCARD14/MALT1 signaling in the pathogenesis of psoriasis and show the potential ofMALT1 inhibition for the treatment of psoriasis.