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- W4366184906 abstract "Skin diseases are characterized by cutaneous cytokine profiles. This includes lupus (IFNγ), atopic dermatitis ([AD], IL-4, IL-13 and IL-22) and psoriasis (IL-17A and IL-22). Janus kinase inhibitors (JAKi) are in the clinic (i.e. abrocitinib, upadacitinib and topical ruxolitinib for AD and deucravacitinib for psoriasis) or in development to treat these diseases. Of these skin diseases, only AD is associated with cutaneous viral infections. Notably, some JAKi (tofacitinib, baracitinib and ruxolitinib) have an increased risk of viral infections. These two observations suggest that specific cytokines alone or in combination with selective JAKi may alter keratinocytes’ susceptibility to viral infections. To evaluate this hypothesis, immortalized (N/TERT2G) and primary human keratinocytes were treated with the aforementioned cytokines alone or in combination with JAKi of varying selectivities and viral susceptibility was assessed by vaccinia virus and herpes simplex virus-1 plaque assays. Only exposure to IL-4+IL-13 or IL-22 significantly (p<0.01) increased keratinocyte susceptibility to both viruses with no effect from IL-17A treatment. Specifically, there was a peak increase of 12.2±3.1-fold (IL-4+IL-13) or a 7.7±2.8-fold (IL-22) in vaccinia virus infection. Conversely, IFNγ significantly reduced viral susceptibility (63.1±64.4-fold, p<0.05). JAK1 selective inhibition reduced IL-4+IL-13 induced viral susceptibility by 44±16% (p<0.05) while IL-22-enhanced viral susceptibility was only inhibited by TYK2 blockade (76±19%, p<0.05). Additionally, IFNγ-mediated viral protection was reversed by JAK2 inhibition (366±294% increase in infection, p=0.056). Cytokines found in AD lesions (IL-4, IL-13 and IL-22) enhance epidermal viral susceptibility and highlight pathways that may make subjects at risk for eczema herpeticum. The increased viral infections observed after use of FDA approved JAKi, especially with JAK2 selectivity, may be due to their inhibitory actions on the antiviral IFN response in KC." @default.
- W4366184906 created "2023-04-19" @default.
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- W4366184906 date "2023-05-01" @default.
- W4366184906 modified "2023-09-26" @default.
- W4366184906 title "1046 JAK inhibition reverses viral susceptibility of keratinocytes in inflammatory environments" @default.
- W4366184906 doi "https://doi.org/10.1016/j.jid.2023.03.1057" @default.
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