Little is known about whether type 1 (IFNγ), 2 (IL-4/
IL-13), or 3 (IL-17A/IL-22)
cytokines affect the susceptibility of keratinocytes (KC) to viruses. These immune pathways predominate in various
skin diseases: lupus,
atopic dermatitis (AD), and
psoriasis, respectively.
Janus kinase inhibitors (JAKi) are approved to treat both AD and
psoriasis, and are in clinical development for lupus. We evaluated whether these
cytokines alter viral susceptibility of KC and determined if this effect is modulated by treatment with JAKi. Viral susceptibility to vaccinia virus (VV) or
herpes simplex virus-1 (HSV-1) ± JAKi was assessed in immortalized and primary human KC pretreated with
cytokines. Exposure to type 2 (IL-4 +
IL-13) or the type 3 (IL-22)
cytokines significantly increased KC viral susceptibility. Specifically, there was a peak increase of 12.2 ± 3.1-fold (IL-4 +
IL-13) or 7.7 ± 2.8-fold (IL-22) in VV
infection as measured by plaque number. Conversely, IFNγ significantly reduced susceptibility to VV (63.1 ± 64.4-fold). The
IL-4 + IL-13-induced viral susceptibility was reduced (44 ± 16%) by JAK1 inhibition, while the IL-22-enhanced viral susceptibility was diminished (76 ± 19%) by TYK2 inhibition. IFNγ-mediated resistance to
viral infection was reversed by JAK2 inhibition (366 ± 294% increase in
infection).
Cytokines expressed in AD skin (IL-4, IL-13, IL-22) increase KC viral susceptibility while IFNγ is protective. JAKi that target JAK1 or TYK2 reversed
cytokine-enhanced viral susceptibility, while JAK2 inhibition reduced the protective effects of IFNγ.