JAK Signaling Is Critically Important in Cytokine-Induced Viral Susceptibility of Keratinocytes

Little is known about whether type 1 (IFN gamma), 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, IFN gamma 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. IFN gamma-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 IFN gamma is protective. JAKi that target JAK1 or TYK2 reversed cytokine-enhanced viral susceptibility, while JAK2 inhibition reduced the protective effects of IFN gamma.

Automated summary

Little is known about the effect of different cytokines on the susceptibility of keratinocytes to viruses. This study found that type 2 and type 3 cytokines increased viral susceptibility of keratinocytes, while IFN gamma reduced susceptibility. The use of JAK inhibitors reversed the cytokine-enhanced viral susceptibility and the protective effects of IFN gamma.