Protective Role for Protease-Activated Receptor-2 against Influenza Virus Pathogenesis via an IFN-γ-Dependent Pathway

Abstract

Protease-activated receptor-2 (PAR₂), a receptor highly expressed in the respiratory tract, can influence inflammation at mucosal surfaces. Although the effects of PAR₂ in the innate immune response to bacterial infection have been documented, knowledge of its role in the context of viral infection is lacking. We thus investigated the role of PAR₂ in influenza pathogenesis in vitro and in vivo. In vitro, stimulation of PAR₂ on epithelial cells inhibited influenza virus type A (IAV) replication through the production of IFN-γ. In vivo, stimulation of PAR₂ using specific agonists protected mice from IAV-induced acute lung injury and death. This effect correlated with an increased clearance of IAV in the lungs associated with increased IFN- γ production and a decreased presence of neutrophils and RANTES release in bronchoalveolar fluids. More importantly, the protective effect of the PAR₂ agonist was totally abrogated in IFN- γ-deficient mice. Finally, compared with wild-type mice, PAR₂-deficient mice were more susceptible to IAV infection and displayed more severe lung inflammation. In these mice higher neutrophil counts and increased RANTES concentration but decreased IFN- γ levels were observed in the bronchoalveolar lavages. Collectively, these results showed that PAR₂ plays a protective role during IAV infection through IFN-γ production and decreased excessive recruitment of inflammatory cells to lung alveoli.