Functional Interplay between Type I and II Interferons Is Essential to Limit Influenza A Virus-Induced Tissue Inflammation

PLoS Pathog. 2016 Jan 5;12(1):e1005378. doi: 10.1371/journal.ppat.1005378. eCollection 2016 Jan.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / immunology
  • Animals
  • Disease Models, Animal
  • Flow Cytometry
  • Immunity, Innate / immunology
  • Influenza A virus / immunology*
  • Interferon Type I / immunology*
  • Interferon-gamma / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Orthomyxoviridae Infections / immunology*
  • Pneumonia / immunology*
  • Respiratory Tract Infections / immunology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / immunology

Substances

  • Interferon Type I
  • Interferon-gamma

Grants and funding

This work was supported by a National Health and Medical Research Council (NHMRC) of Australia Project Grant (APP1051742). WJB is supported by a NHMRC Centre for Research Excellence in Tuberculosis Control grant (APP1043225). NB is supported by an Australian Postgraduate Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.