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UBE2L3 Reduces TRIM21 Expression and IL-1β Secretion in Epidermal Keratinocytes and Improves Psoriasis-Like Skin

Published:December 08, 2022DOI:https://doi.org/10.1016/j.jid.2022.10.016
      Proinflammatory cytokines, such as IL-1β, are important mediators of psoriasis. UBE2L3, an E2 enzyme, is thought to be an indirect target of IL-1β secretion by binding to ubiquitin ligases such as TRIM21. However, its role in psoriasis remains unknown. In this study, we found that UBE2L3 expression was decreased in psoriatic epidermis, whereas caspase 1 and IL-1β signaling were strongly activated. When normal human epidermal keratinocytes were stimulated with nigericin, adenosine triphosphate, and poly(dA:dT), downregulation of UBE2L3 and increased secretion of IL-1β were observed. Treatment with a caspase 1 inhibitor reversed the decrease in the level of UBE2L3. In addition, UBE2L3 overexpression reduced TRIM21, decreased signal transducer and activator of transcription 3 pathway activity, and reduced the level of the IL-1β precursor (pro‒IL-1β). Consistently, silencing UBE2L3 enhanced TRIM21 expression, signal transducer and activator of transcription 3 activation, and pro‒IL-1β production. Finally, in an imiquimod-induced mouse model, UBE2L3 reduction and caspase 1 activation were localized in the epidermis, whereas overexpression of UBE2L3 ameliorated psoriasis-like lesions and reduced pro‒IL-1β and mature IL-1β levels in the epidermis. Thus, UBE2L3 may be a protective biomarker that regulates IL-1β and inhibits TRIM21 in the epidermis of psoriasis.

      Graphical abstract

      Abbreviations:

      ATP (adenosine triphosphate), Casp1 (caspase 1), IMQ (imiquimod), KC (keratinocyte), LPS (lipopolysaccharide), NHEK (normal human epidermal keratinocyte), PLEK (psoriatic lesional epidermal keratinocyte), pro-Casp1 (caspase 1 precursor), siRNA (small interfering RNA), STAT3 (signal transducer and activator of transcription 3)
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      Supplementary Reference

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