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Linear Ubiquitination in Keratinocytes Amplifies Psoriatic inflammation via TNF-α/NF-κB Signaling [RNA-seq 2]

ABSTRACT: Psoriasis is a chronic inflammatory skin disorder driven by dysregulated immune signaling and keratinocyte activation. While the importance of proinflammatory cytokines such as TNF-α, 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-1LΔRING1) with enhanced LUBAC activity. In the imiquimod-induced psoriasis model, HOIL-1LΔRING1 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-α/NF-κB signaling, and TNF-α 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-α 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE305680 | GEO | 2025/12/31

REPOSITORIES: GEO

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Linear Ubiquitination in Keratinocytes Amplifies Psoriatic inflammation via TNF-α/NF-κB Signaling [RNA-seq]

Project description:Psoriasis is a chronic inflammatory skin disorder driven by dysregulated immune signaling and keratinocyte activation. While the importance of proinflammatory cytokines such as TNF-α, 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-1LΔRING1) with enhanced LUBAC activity. In the imiquimod-induced psoriasis model, HOIL-1LΔRING1 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-α/NF-κB signaling, and TNF-α 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-α 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.

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