Interferon-γ promotes monocyte-mediated lung injury during influenza infection
Taylor Schmit, Kai Guo, Jitendra Kumar Tripathi, Zhihan Wang, Brett A. McGregor, Mitch Klomp, Ganesh Ambigapathy, Ramkumar Mathur, Junguk Hur, Michael E. Pichichero, Jay K. Kolls, M. Nadeem Khan
Abstract
Influenza A virus (IAV) infection triggers an exuberant host response that promotes acute lung injury. However, the host response factors that promote the development of a pathologic inflammatory response to IAV remain incompletely understood. In this study, we identify an interferon-γ (IFN-γ)-regulated subset of monocytes, CCR2+ monocytes, as a driver of lung damage during IAV infection. IFN-γ regulates the recruitment and inflammatory phenotype of CCR2+ monocytes, and mice deficient in CCR2 (CCR2−/−) or IFN-γ (IFN-γ−/−) exhibit reduced lung inflammation, pathology, and disease severity. Adoptive transfer of wild-type (WT) (IFN-γR1+/+) but not IFN-γR1−/− CCR2+ monocytes restore the WT-like pathological phenotype of lung damage in IAV-infected CCR2−/− mice. CD8+ T cells are the main source of IFN-γ in IAV-infected lungs. Collectively, our data highlight the requirement of IFN-γ signaling in the regulation of CCR2+ monocyte-mediated lung pathology during IAV infection.