Abstract
BackgroundInfluenza attacks the epithelium of the lung, causing cell death and disruption of the epithelial barrier leading to fluid buildup in the lung and impairment of gas exchange. Limited treatment options for severe influenza pneumonia prioritize the need for the discovery of effective therapies. IL-22 is a cytokine that promotes tissue integrity and has strong promise as a treatment option. While research has been focused on the cytokine itself, there is limited understanding of the regulation of the IL-22 receptor (IL-22Ra1) at the epithelial surface during infection.MethodsIL-22Ra1 levels were measured by qRT-PCR, western blot and immunofluorescence following H1N1 influenza infection (A/PR/8/34 H1N1) or synthetic TLR3 mimetic, Poly (I:C). Regulation of the receptor was determined using STAT inhibitors (STAT1, STAT3 and PanSTAT inhibitors), TLR3 inhibition, and neutralization of interferon alpha receptor 2 (IFNAR2). Significance was determined by a p-value of greater than 0.05. Significance between two groups was measured using unpaired t-test and significance between more than two groups was measured using one-way ANOVA with Tukey Multiple Comparison Test.ResultsHere we show both in vivo and in vitro that IL-22Ra1 was induced as early as 24 h after influenza (H1N1 PR8) infection. This induction was triggered by toll-like receptor 3 (TLR3) as a TLR3 mimetic [Poly (I:C)] also induced IL-22Ra1 and inhibition of endosomal formation required for TLR3 function inhibited this process. This upregulation was dependent upon IFNβ signaling through STAT1. Importantly, induction of IL-22Ra1 significantly increased IL-22 signaling as evidenced by pSTAT3 levels following IL-22 treatment.ConclusionCollectively, these data suggest epithelial cells may optimize the beneficial effects of IL-22 through the induction of the IL-22 receptor during viral infection in the lung.
Highlights
Influenza attacks the epithelium of the lung, causing cell death and disruption of the epithelial barrier leading to fluid buildup in the lung and impairment of gas exchange
IL-22Ra1 induction following H1N1 infection is toll-like receptor 3 (TLR3) mediated We have reported that IL-22Ra1 is significantly induced in both the airways and lung parenchyma following H1N1 infection [10]
To determine if IL-22Ra1 is induced through TLR3, C57Bl/6 mice were infected with influenza (H1N1 PR/8/34 H1N1 (PR8)) or treated with a synthetic double stranded RNA (dsRNA) TLR3 agonist Poly(I:C)
Summary
Influenza attacks the epithelium of the lung, causing cell death and disruption of the epithelial barrier leading to fluid buildup in the lung and impairment of gas exchange. While research has been focused on the cytokine itself, there is limited understanding of the regulation of the IL-22 receptor (IL-22Ra1) at the epithelial surface during infection. It is an RNA virus that is highly adapted to infect the pulmonary epithelial cells through binding to sialic acid residues. In the case of influenza, it is the TLR3 that acts as an early warning system for the infected epithelial cells [6]. TLR3 recognizes double stranded RNA (dsRNA), leading to signaling pathways that drive the production of Type I interferons (IFNs) [7]. Release of IFNα and IFNβ act upon neighboring epithelial cells to alert them to the infection, instigate intracellular antiviral pathways as well as initiate the innate and adaptive immune responses [8]
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