Abstract
Purpose :
HSV induced stromal keratitis (SK) is one of the leading causes of infectious blindness in the world. Although the role of inflammatory cytokines is well defined in SK, the role of a regulatory cytokine IL-27 has not been explored yet. In this study, using murine model of SK, we investigated the role of IL-27 response in cornea after HSV infection. Further, we explored IL-27- mediated regulation of inflammation and antiviral responses during corneal HSV infection.
Methods :
IL-27RKO and C57BL/6NJ mice were ocularly infected with HSV. Eye swabs were collected on days 1, 3 and 5 post-infection (pi) for viral titration. The progression of SK lesions were scored on days 8, 11 and 14 pi. Further, the infiltration of neutrophils, macrophages and effector T cells in cornea, lymph node and spleen were analyzed on days 2 and 15 pi. Additionally, bone marrow-derived macrophages from IL-27RKO and C57BL/6NJ mice were cultured ex vivo to investigate IL-27 mediated anti-inflammatory and antiviral responses.
Results :
Our data suggested an increased IL-27 production after corneal HSV infection which is mainly produced by dendritic cells and macrophages. In addition, IL-27RKO mice showed significantly increased SK pathology compared to control animals. The increased SK severity in IL-27RKO mice was mainly driven by enhanced migration of neutrophils, macrophages and Th1 cells to cornea. Mechanistically, IL-27 mediated signaling is critical for induction of type-1 interferon (IFN) responses by macrophages after HSV infection. In accordance, we observed significantly higher viral load in the corneas of IL-27RKO mice when compared to the control mice. Further, when stimulated with HSV our data showed reduced IFN-β production and increased viral titers in IL-27RKO macrophages.
Conclusions :
Our data indicate that increased IL-27 response is critical for optimum production of IFN-β by macrophages and thus viral clearance. Further IL-27 plays a regulatory role during SK pathology by modulating Th1 cell differentiation and migration. Collectively, our results indicate that modulating IL-27-mediated responses may represent a useful therapeutic approach to control viral replication and inflammation during HSV induced SK pathology.
This is a 2021 ARVO Annual Meeting abstract.