1887

Abstract

The role of the macrophage in influenza virus infection is complex. Macrophages are critical for resolution of influenza virus infections but implicated in morbidity and mortality in severe infections. They can be infected with influenza virus and consequently macrophage infection is likely to have an impact on the host immune response. Macrophages display a range of functional phenotypes, from the prototypical pro-inflammatory classically activated cell to alternatively activated anti-inflammatory macrophages involved in immune regulation and wound healing. We were interested in how macrophages of different phenotype respond to influenza virus infection and therefore studied the infection of bone marrow-derived macrophages (BMDMs) of classical and alternative phenotype . Our results show that alternatively activated macrophages are more readily infected and killed by the virus than classically activated. Classically activated BMDMs express the pro-inflammatory markers inducible nitric oxide synthase (iNOS) and TNF-α, and TNF-α expression was further upregulated following infection. Alternatively activated macrophages express Arginase-1 and CD206; however, following infection, expression of these markers was downregulated whilst expression of iNOS and TNF-α was upregulated. Thus, infection can override the anti-inflammatory state of alternatively activated macrophages. Importantly, however, this results in lower levels of pro-inflammatory markers than those produced by classically activated cells. Our results showed that macrophage phenotype affects the inflammatory macrophage response following infection, and indicated that modulating the macrophage phenotype may provide a route to develop novel strategies to prevent and treat influenza virus infection.

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2015-10-01
2024-03-29
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References

  1. Cheung C.Y., Poon L.L.M., Lau A.S., Luk W., Lau Y.L., Shortridge K.F., Gordon S., Guan Y., Peiris J.S.M. 2002; Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease?. Lancet 360:1831–1837 [View Article][PubMed]
    [Google Scholar]
  2. Drapier J.C., Wietzerbin J., Hibbs J.B. Jr 1988; Interferon-gamma and tumor necrosis factor induce the l-arginine-dependent cytotoxic effector mechanism in murine macrophages. Eur J Immunol 18:1587–1592 [View Article][PubMed]
    [Google Scholar]
  3. Farrell A.J., Blake D.R. 1996; Nitric oxide. Ann Rheum Dis 55:7–20 [View Article][PubMed]
    [Google Scholar]
  4. Gao J.J., Filla M.B., Fultz M.J., Vogel S.N., Russell S.W., Murphy W.J. 1998; Autocrine/paracrine IFN-alphabeta mediates the lipopolysaccharide-induced activation of transcription factor Stat1alpha in mouse macrophages: pivotal role of Stat1alpha in induction of the inducible nitric oxide synthase gene. J Immunol 161:4803–4810[PubMed]
    [Google Scholar]
  5. Geller D.A., de Vera M.E., Russell D.A., Shapiro R.A., Nussler A.K., Simmons R.L., Billiar T.R. 1995; A central role for IL-1 beta in the in vitro and in vivo regulation of hepatic inducible nitric oxide synthase. IL-1 beta induces hepatic nitric oxide synthesis. J Immunol 155:4890–4898[PubMed]
    [Google Scholar]
  6. Gessani S., Belardelli F. 1998; IFN-gamma expression in macrophages and its possible biological significance. Cytokine Growth Factor Rev 9:117–123 [View Article][PubMed]
    [Google Scholar]
  7. Gordon S. 2003; Alternative activation of macrophages. Nat Rev Immunol 3:23–35 [View Article][PubMed]
    [Google Scholar]
  8. Gordon S., Taylor P.R. 2005; Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964 [View Article][PubMed]
    [Google Scholar]
  9. Hoeve M.A., Nash A.A., Jackson D., Randall R.E., Dransfield I. 2012; Influenza virus A infection of human monocyte and macrophage subpopulations reveals increased susceptibility associated with cell differentiation. PLoS One 7:e29443 [View Article][PubMed]
    [Google Scholar]
  10. Huang S., Hendriks W., Althage A., Hemmi S., Bluethmann H., Kamijo R., Vilcek J., Zinkernagel R.M., Aguet M. 1993; Immune response in mice that lack the interferon-gamma receptor. Science 259:1742–1745 [View Article][PubMed]
    [Google Scholar]
  11. Kobasa D., Jones S.M., Shinya K., Kash J.C., Copps J., Ebihara H., Hatta Y., Kim J.H., Halfmann P., other authors. 2007; Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature 445:319–323 [View Article][PubMed]
    [Google Scholar]
  12. Korteweg C., Gu J. 2008; Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. Am J Pathol 172:1155–1170 [View Article][PubMed]
    [Google Scholar]
  13. Londrigan S.L., Turville S.G., Tate M.D., Deng Y.M., Brooks A.G., Reading P.C. 2011; N-linked glycosylation facilitates sialic acid-independent attachment and entry of influenza A viruses into cells expressing DC-SIGN or L-SIGN. J Virol 85:2990–3000 [View Article][PubMed]
    [Google Scholar]
  14. Ma X., Chow J.M., Gri G., Carra G., Gerosa F., Wolf S.F., Dzialo R., Trinchieri G. 1996; The interleukin 12 p40 gene promoter is primed by interferon gamma in monocytic cells. J Exp Med 183:147–157 [View Article][PubMed]
    [Google Scholar]
  15. Matlin K.S., Reggio H., Helenius A., Simons K. 1981; Infectious entry pathway of influenza virus in a canine kidney cell line. J Cell Biol 91:601–613 [View Article][PubMed]
    [Google Scholar]
  16. Misharin A.V., Morales-Nebreda L., Mutlu G.M., Budinger G.R., Perlman H. 2013; Flow cytometric analysis of macrophages and dendritic cell subsets in the mouse lung. Am J Respir Cell Mol Biol 49:503–510 [View Article][PubMed]
    [Google Scholar]
  17. Montaner L.J., da Silva R.P., Sun J., Sutterwala S., Hollinshead M., Vaux D., Gordon S. 1999; Type 1 and type 2 cytokine regulation of macrophage endocytosis: differential activation by IL-4/IL-13 as opposed to IFN-gamma or IL-10. J Immunol 162:4606–4613[PubMed]
    [Google Scholar]
  18. Nicol M.Q., Dutia B.M. 2014; The role of macrophages in influenza A virus infection. Future Virol 9:847–862 [View Article]
    [Google Scholar]
  19. Nicol M.Q., Ligertwood Y., Bacon M.N., Dutia B.M., Nash A.A. 2012; A novel family of peptides with potent activity against influenza A viruses. J Gen Virol 93:980–986 [View Article][PubMed]
    [Google Scholar]
  20. Perrone L.A., Plowden J.K., García-Sastre A., Katz J.M., Tumpey T.M. 2008; H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice. PLoS Pathog 4:e1000115[PubMed] [CrossRef]
    [Google Scholar]
  21. Pinheiro J.C., Bates D.M. 2004; Mixed-Effects Models in S and S-PLUS. , 3rd Edition. Springer; New York:
    [Google Scholar]
  22. Raveh D., Kruskal B.A., Farland J., Ezekowitz R.A. 1998; Th1 and Th2 cytokines cooperate to stimulate mannose-receptor-mediated phagocytosis. J Leukoc Biol 64:108–113[PubMed]
    [Google Scholar]
  23. Reading P.C., Miller J.L., Anders E.M. 2000; Involvement of the mannose receptor in infection of macrophages by influenza virus. J Virol 74:5190–5197 [View Article][PubMed]
    [Google Scholar]
  24. Rodgers B., Mims C.A. 1981; Interaction of influenza virus with mouse macrophages. Infect Immun 31:751–757[PubMed]
    [Google Scholar]
  25. Rodgers B.C., Mims C.A. 1982; Influenza virus replication in human alveolar macrophages. J Med Virol 9:177–184 [View Article][PubMed]
    [Google Scholar]
  26. Saito F., Ito T., Connett J.M., Schaller M.A., Carson W.F. IV, Hogaboam C.M., Rochford R., Kunkel S.L. 2013; MHV68 latency modulates the host immune response to influenza A virus. Inflammation 36:1295–1303 [View Article][PubMed]
    [Google Scholar]
  27. Schroder K., Hertzog P.J., Ravasi T., Hume D.A. 2004; Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 75:163–189 [View Article][PubMed]
    [Google Scholar]
  28. Short K.R., Brooks A.G., Reading P.C., Londrigan S.L. 2012; The fate of influenza A virus after infection of human macrophages and dendritic cells. J Gen Virol 93:2315–2325 [View Article][PubMed]
    [Google Scholar]
  29. Skehel J.J., Wiley D.C. 2000; Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu Rev Biochem 69:531–569 [View Article][PubMed]
    [Google Scholar]
  30. Stein M., Keshav S., Harris N., Gordon S. 1992; Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med 176:287–292 [View Article][PubMed]
    [Google Scholar]
  31. Tate M.D., Pickett D.L., van Rooijen N., Brooks A.G., Reading P.C. 2010; Critical role of airway macrophages in modulating disease severity during influenza virus infection of mice. J Virol 84:7569–7580 [View Article][PubMed]
    [Google Scholar]
  32. Tate M.D., Schilter H.C., Brooks A.G., Reading P.C. 2011; Responses of mouse airway epithelial cells and alveolar macrophages to virulent and avirulent strains of influenza A virus. Viral Immunol 24:77–88 [View Article][PubMed]
    [Google Scholar]
  33. Tumpey T.M., García-Sastre A., Taubenberger J.K., Palese P., Swayne D.E., Pantin-Jackwood M.J., Schultz-Cherry S., Solórzano A., Van Rooijen N., other authors. 2005; Pathogenicity of influenza viruses with genes from the 1918 pandemic virus: functional roles of alveolar macrophages and neutrophils in limiting virus replication and mortality in mice. J Virol 79:14933–14944 [View Article][PubMed]
    [Google Scholar]
  34. Upham J.P., Pickett D., Irimura T., Anders E.M., Reading P.C. 2010; Macrophage receptors for influenza A virus: role of the macrophage galactose-type lectin and mannose receptor in viral entry. J Virol 84:3730–3737 [View Article][PubMed]
    [Google Scholar]
  35. van Riel D., Leijten L.M., van der Eerden M., Hoogsteden H.C., Boven L.A., Lambrecht B.N., Osterhaus A.D., Kuiken T. 2011; Highly pathogenic avian influenza virus H5N1 infects alveolar macrophages without virus production or excessive TNF-alpha induction. PLoS Pathog 7:e1002099 [View Article][PubMed]
    [Google Scholar]
  36. Varin A., Mukhopadhyay S., Herbein G., Gordon S. 2010; Alternative activation of macrophages by IL-4 impairs phagocytosis of pathogens but potentiates microbial-induced signalling and cytokine secretion. Blood 115:353–362 [View Article][PubMed]
    [Google Scholar]
  37. Wang J., Li F., Sun R., Gao X., Wei H., Li L.J., Tian Z. 2013; Bacterial colonization dampens influenza-mediated acute lung injury via induction of M2 alveolar macrophages. Nat Commun 4:2106[PubMed]
    [Google Scholar]
  38. Webster R.G., Govorkova E.A. 2014; Continuing challenges in influenza. Ann N Y Acad Sci 1323:115–139 [View Article][PubMed]
    [Google Scholar]
  39. Yu W.C., Chan R.W., Wang J., Travanty E.A., Nicholls J.M., Peiris J.S., Mason R.J., Chan M.C. 2011; Viral replication and innate host responses in primary human alveolar epithelial cells and alveolar macrophages infected with influenza H5N1 and H1N1 viruses. J Virol 85:6844–6855 [View Article][PubMed]
    [Google Scholar]
  40. Zhou J., Law H.K., Cheung C.Y., Ng I.H., Peiris J.S., Lau Y.L. 2006; Differential expression of chemokines and their receptors in adult and neonatal macrophages infected with human or avian influenza viruses. J Infect Dis 194:61–70 [View Article][PubMed]
    [Google Scholar]
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