Linear Ubiquitination in Keratinocytes Amplifies Psoriatic inflammation via TNF-a/NF-?B Signaling [RNA-seq]

Psoriasis is a chronic inflammatory skin disorder driven by dysregulated immune signaling and keratinocyte activation. While the importance of proinflammatory cytokines such as TNF-a, IL-23, and IL-17 in psoriasis is well established, the upstream mechanisms amplifying these pathways, particularly within keratinocytes, remain incompletely defined. Here, we investigate the role of linear ubiquitination—a post-translational modification catalyzed by the linear ubiquitin chain assembly complex (LUBAC)—in psoriasis pathogenesis using a transgenic mouse model (HOIL-1L?RING1) with enhanced LUBAC activity. In the imiquimod-induced psoriasis model, HOIL-1L?RING1 mice exhibited exacerbated skin inflammation characterized by increased epidermal thickness, leukocyte infiltration, and elevated expression of Tnf and Il23a. Transcriptomic and pharmacologic analyses showed that linear ubiquitination amplified TNF-a/NF-?B signaling, and TNF-a blockade ameliorated disease severity. BM chimera experiments demonstrated that this effect was mediated by radio-resistant skin cells, particularly keratinocytes. Flow cytometry and in vitro assays confirmed that keratinocyte-intrinsic linear ubiquitination promotes TNF-a production, which was suppressed by a LUBAC inhibitor. Finally, analyses of human psoriatic skin confirmed elevated linear ubiquitination and LUBAC component expression in keratinocytes. These findings identify linear ubiquitination in keratinocytes as a key amplifier of psoriatic inflammation and a potential therapeutic target. Overall design: RNA-seq of ear skin from wild-type and HOIL1 ?RING1 mice 1 day after imiquimod treatment.