| First Author | Lorscheid S | Year | 2019 |
| Journal | JCI Insight | Volume | 4 |
| Issue | 22 | PubMed ID | 31622280 |
| Mgi Jnum | J:291029 | Mgi Id | MGI:6407694 |
| Doi | 10.1172/jci.insight.130835 | Citation | Lorscheid S, et al. (2019) Keratinocyte-derived IkappaBzeta drives psoriasis and associated systemic inflammation. JCI Insight 4(22) |
| abstractText | The transcriptional activator IkappaBzeta is a key regulator of psoriasis, but which cells mediate its pathogenic effect remains unknown. Here we found that IkappaBzeta expression in keratinocytes triggers not only skin lesions but also systemic inflammation in mouse psoriasis models. Specific depletion of IkappaBzeta in keratinocytes was sufficient to suppress the induction of imiquimod- or IL-36-mediated psoriasis. Moreover, IkappaBzeta ablation in keratinocytes prevented the onset of psoriatic lesions and systemic inflammation in keratinocyte-specific IL-17A-transgenic mice. Mechanistically, this psoriasis protection was mediated by IkappaBzeta deficiency in keratinocytes abrogating the induction of specific proinflammatory target genes, including Cxcl5, Cxcl2, Csf2, and Csf3, in response to IL-17A or IL-36. These IkappaBzeta-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 IkappaBzeta as key mediators of psoriasis and psoriasis-related systemic inflammation. |
