Defining the Role of Type I Interferon Signaling in the Increased Accumulation of Versican in Lungs of Mice Exposed to Influenza Infection
Authors: Brune Jourdan , Chang Mary , Felgenhauer Jessica , Johnson Brian , Larmore Megan , Altemeier William , Frevert Charles 
Published: June 2021

The accumulation of versican in the extracellular matrix (ECM) has been described as part of the innate immune response to viral lung infection. However, the mechanism(s) regulating versican expression during influenza infection are not understood. Previous work has identified both the β‐catenin/T‐cell factor pathway and the TLR/Trif/Type I interferon (IFN) receptor pathway as controlling versican expression in stromal cells and macrophages respectively. The goal of this study, is to investigate the role of Type I IFN receptor signaling in directing versican accumulation in the lungs during influenza infection.

Versican is a proteoglycan that plays an immunomodulatory role in the innate immune response. During influenza infection, creation of a versican enriched ECM coincides with retention of leukocytes in lungs. Our published studies show that versican impacts leukocyte phenotype; macrophage‐derived versican has anti‐inflammatory properties; Type I IFN receptor signaling pathway directs versican synthesis in macrophages; and versican is necessary for Type I IFN production by macrophages. Based on these findings, we hypothesized that IFNβ expression levels should increase prior to versican expression and accumulation and coincide with significant influenza disease burden.

We used qPCR, immunohistochemistry, and quantitative digital pathology of whole lung tissue to evaluate the lungs of C57Bl6/J mice infected with H1N1 A/PR/8/34 influenza. Tissues were harvested on days 3, 6, 9 and 12 post instillation to determine changes in cytokine and versican expression and versican accumulation overtime. Analysis showed that versican mRNA expression was bimodal with significant increases on days 3 and 9. However, significant increases in immunostaining for the versican β‐glycosaminoglycan domain was seen on days 6, 9, and 12 and corresponded to significant weight loss in mice on days 6 and 9. To better understand the involvement of Type I IFN directed expression of versican, we measured IFNβ expression levels and found that they were significantly increased on day 6, after the initial increase in versican mRNA expression on day 3 and coinciding with the primary increase in versican tissue accumulation. These studies suggest that Type I IFN signaling plays an important role in the expression and accumulation of versican on day 9 after influenza infection.

Taken together with what is known about versican regulation by Type I IFNs, these findings suggest that the Type I IFN pathway may be important in the regulation of versican expression late in influenza disease progression. Studies in conditional cell specific versican deficient mice will clarify the role of Type I IFNs in regulating versican expression; the cellular source of versican expression following activation of Type I IFN receptors; and the role of versican in modulating the immune response to influenza infection. Additional studies are needed to determine whether β‐catenin signaling also contributes to pulmonary versican accumulation following influenza infection.

Support or Funding Information

NIH/NIAID 1R01AI136468‐01

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.