P72 The role of the transcription factor Bcl11b in IL-17, IL-23 and/or TNF-induced activation of the canonical and non-canonical NF-κB pathways in psoriatic keratinocytes

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Abstract Bcl11b (CTIP2) is a crucial transcription factor involved in the differentiation processes across various cell types, including T cells and keratinocytes. It functions both as a transcriptional repressor and activator, interacting with complexes such as NuRD and proteins like p300. Bcl11b is significantly expressed in skin and immune cells suggesting its potential involvement in diseases like psoriasis, which is characterized by hyperproliferation and aberrant differentiation of keratinocytes alongside immune cell infiltration and cytokine release. However, the mechanism underlying the role of Bcl11b in the pathogenesis of psoriasis remains unidentified. To elucidate Bcl11b’s role in psoriasis by analysing its expression and correlated pathways through meta-analysis of sequencing-based transcriptome profiles and by functional assays in normal and genetically engineered keratinocytes under inflammatory conditions. RNA-sequencing datasets from psoriatic and healthy skin samples were processed and analysed for differential expression of transcription factors, with a focus on Bcl11b. Pearson correlation analysis identified genes correlated with Bcl11b expression. Enrichment and pathway analyses were conducted using Enrichr. Functional studies involved Bcl11b knockdown in HaCaT keratinocytes via CRISPRi, followed by cytokine stimulation including IL-17A, IL-23, TNF-α and the combinations. The activation of canonical and non-canonical NF-κB pathways was assessed. Downregulation of Bcl11b in psoriatic lesions was confirmed. Correlated genes were enriched in pathways involving IL-17A, IL-23 and TNF-α signalling. Knockdown of Bcl11b in keratinocytes resulted in morphological changes indicative of incomplete differentiation and reduced proliferation. Under cytokine-driven inflammatory conditions, canonical NF-κB pathway activation was impaired in Bcl11b KD cells, while non-canonical NF-κB pathway activation was dependent on IL-17A and the combination of IL-23/TNF-α in these KD cells. These data highlight the pivotal role of Bcl11b in the proinflammatory cytokine-induced regulation of the NF-κB signalling pathways. Absence of Bcl11b results in abnormal keratinocyte behaviour associated with psoriasis. Our data suggest that key proinflammatory cytokines in psoriasis act differently on Bcl11b associated activation of the NF-kB pathways.