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

Abstract

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.

Oclacitinib and Myxoma Virus Therapy in Dogs with High Grade Soft Tissue Sarcoma

“…When mRNA transcripts were evaluated, the JAK-STAT and cytokine/chemokine pathway signaling scores increased in healthy canine fibroblasts following MYXV and MYXV∆SERP2 inoculation, but decreased in two canine cancer cell cultures (STS-1 and STS-2). The importance of JAK-STAT signaling in the inhibition of viral replication is well established in human cells, including human keratinocyte susceptibility to poxvirus (vaccinia virus) infection [61]. This study suggests that it is also important in canine cells.…”

Oclacitinib and Myxoma Virus Therapy in Dogs with High-Grade Soft Tissue Sarcoma

“…When mRNA transcripts were evaluated, the JAK-STAT and cytokine/chemokine pathway signaling scores increased in healthy canine fibroblasts following MYXV and MYXVΔSERP2 inoculation, but decreased in two canine cancer cell cultures (STS-1 and STS-2). The importance of JAK-STAT signaling in the inhibition of viral replication is well established in human cells, including human keratinocyte susceptibility to poxvirus (vaccinia virus) infection [ 61 ]. This study suggests that it is also important in canine cells.…”