title: Functional Interplay between Type I and II Interferons Is Essential to Limit Influenza A Virus-Induced Tissue Inflammation.
abstract: Host control of influenza A virus (IAV) is associated with exuberant pulmonary inflammation characterized by the influx of myeloid cells and production of proinflammatory cytokines including interferons (IFNs). It is unclear, however, how the immune system clears the virus without causing lethal immunopathology. Here, we demonstrate that in addition to its known anti-viral activity, STAT1 signaling coordinates host inflammation during IAV infection in mice. This regulatory mechanism is dependent on both type I IFN and IFN-γ receptor signaling and, importantly, requires the functional interplay between the two pathways. The protective function of type I IFNs is associated with not only the recruitment of classical inflammatory Ly6Chi monocytes into IAV-infected lungs, but also the prevention of excessive monocyte activation by IFN-γ. Unexpectedly, type I IFNs preferentially regulate IFN-γ signaling in Ly6Clo rather than inflammatory Ly6Chi mononuclear cell populations. In the absence of type I IFN signaling, Ly6Clo monocytes/macrophages, become phenotypically and functionally more proinflammatory than Ly6Chi cells, revealing an unanticipated function of the Ly6Clo mononuclear cell subset in tissue inflammation. In addition, we show that type I IFNs employ distinct mechanisms to regulate monocyte and neutrophil trafficking. Type I IFN signaling is necessary, but not sufficient, for preventing neutrophil recruitment into the lungs of IAV-infected mice. Instead, the cooperation of type I IFNs and lymphocyte-produced IFN-γ is required to regulate the tissue neutrophilic response to IAV. Our study demonstrates that IFN interplay links innate and adaptive anti-viral immunity to orchestrate tissue inflammation and reveals an additional level of complexity for IFN-dependent regulatory mechanisms that function to prevent excessive immunopathology while preserving anti-microbial functions.
authors.affiliation: Immunology and Host Defense Group, Discipline of Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.|Mycobacterial Research Program, The Centenary Institute, Camperdown, New South Wales, Australia.
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Stifter
authors.affiliation: Immunology and Host Defense Group, Discipline of Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Nayan
authors.initials: N
authors.lastname: Bhattacharyya
authors.affiliation: Immunology and Host Defense Group, Discipline of Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Roman
authors.initials: R
authors.lastname: Pillay
authors.affiliation: Mycobacterial Research Program, The Centenary Institute, Camperdown, New South Wales, Australia.
authors.forename: Manuela
authors.initials: M
authors.lastname: Flórido
authors.affiliation: Mycobacterial Research Program, The Centenary Institute, Camperdown, New South Wales, Australia.|Microbial Pathogenesis and Immunity Group, Discipline of Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: James A
authors.initials: JA
authors.lastname: Triccas
authors.affiliation: Mycobacterial Research Program, The Centenary Institute, Camperdown, New South Wales, Australia.|Discipline of Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.|Department of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Warwick J
authors.initials: WJ
authors.lastname: Britton
authors.affiliation: Immunology and Host Defense Group, Discipline of Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.|Mycobacterial Research Program, The Centenary Institute, Camperdown, New South Wales, Australia.
authors.forename: Carl G
authors.initials: CG
authors.lastname: Feng
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology; D009980:Influenza A virus / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D011014:Pneumonia / Q000276:immunology*; D012141:Respiratory Tract Infections / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology
chemical_list: D007370:Interferon Type I; D007371:Interferon-gamma