Keratinocyte-derived IκBζ drives psoriasis and associated systemic inflammation.

The transcriptional activator I kappa B zeta is a key regulator of psoriasis, but which cells mediate its pathogenic effect remains unknown. Here we found that I kappa B zeta expression in keratinocytes triggers not only skin lesions but also systemic inflammation in mouse psoriasis models. Specific depletion of I kappa B zeta in keratinocytes was sufficient to suppress the induction of imiquimod- or 1L-36-mediated psoriasis. Moreover, I kappa B zeta ablation in keratinocytes prevented the onset of psoriatic lesions and systemic inflammation in keratinocyte-specific 1L-17A-transgenic mice. Mechanistically, this psoriasis protection was mediated by I kappa B zeta deficiency in keratinocytes abrogating the induction of specific proinflammatory target genes, including Excl5, Excl2, Csf2, and tsf3, in response to 1L-17A or 1L-36. These I kappa B zeta-dependent genes trigger the generation and recruitment of neutrophils and monocytes that are needed for skin inflammation. Consequently, our data uncover a surprisingly pivotal role of keratinocytes and keratinocyte-derived I kappa B zeta as key mediators of psoriasis and psoriasis-related systemic inflammation.