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Leukotriene B4–type I interferon axis regulates macrophage-mediated disease tolerance to influenza infection

Nature Microbiology volume 4, pages 1389–1400 (2019)Cite this article

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Abstract

Host defence against influenza A virus (IAV) infection depends not only on host resistance to eliminate the virus, but also disease tolerance to limit lung tissue damage and maintain pulmonary function. Fatal IAV infections are frequently the result of a maladaptive immune response that compromises disease tolerance rather than host resistance to infection. Here, we show that the leukotriene B4 (LTB4)–type I interferon (IFN) axis promotes a distinct mechanism of disease tolerance to pulmonary IAV infection. We demonstrate that mice genetically deficient in LTB4 signalling (Blt1R−/−) are more susceptible to IAV infection compared to control mice, despite similar pulmonary viral loads. The increased susceptibility of Blt1R−/− mice is associated with an accumulation of inflammatory monocyte-derived macrophages (IMMs) causing increased lung immunopathology. We mechanistically define that LTB4 signalling via the BLT1 receptor enhances the activation of the type I IFN-α/β receptor (IFNAR)/ and signal transducer and activator of transcription 1 (STAT1), which leads to IFN-α production by interstitial macrophages to suppresse in situ IMM proliferation. Importantly, the delivery of a single dose of LTB4 at the peak viral load reduces IMM proliferation, controls tissue damage and increases survival without affecting host resistance to IAV. These results reveal an unexpected anti-inflammatory role of LTB4 in disease tolerance to IAV infection.

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Fig. 1: LTB4–BLT1R axis limits IAV-induced immunopathology.
Fig. 2: LTB4–BLT1R axis regulates in situ macrophage proliferation.
Fig. 3: IFN-I is required to regulate IMM proliferation.
Fig. 4: Blt1R−/− interstitial macrophages are impaired in IFN-α production.
Fig. 5: LTB4–BLT1R axis enhances STAT1 activation to produce IFN-α.
Fig. 6: Exogenous LTB4 treatment enhances disease tolerance and survival following IAV infection.

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Data availability

The data that support the findings of this study are available from the corresponding author upon request.

References

  1. Soares, M. P., Teixeira, L. & Moita, L. F. Disease tolerance and immunity in host protection against infection. Nat. Rev. Immunol. 17, 83–96 (2017).

    Article  CAS  Google Scholar 

  2. Medzhitov, R., Schneider, D. S. & Soares, M. P. Disease tolerance as a defense strategy. Science 335, 936–941 (2012).

    Article  CAS  Google Scholar 

  3. Perrone, L. A., Plowden, J. K., Garcia-Sastre, A., Katz, J. M. & Tumpey, T. M. 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 (2008).

    Article  Google Scholar 

  4. Short, K. R. et al. Influenza virus damages the alveolar barrier by disrupting epithelial cell tight junctions. Eur. Respir. J. 47, 954–966 (2016).

    Article  CAS  Google Scholar 

  5. Lin, K. L., Suzuki, Y., Nakano, H., Ramsburg, E. & Gunn, M. D. CCR2+ monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality. J. Immunol. 180, 2562–2572 (2008).

    Article  CAS  Google Scholar 

  6. Herold, S. et al. Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand. J. Exp. Med. 205, 3065–3077 (2008).

    Article  CAS  Google Scholar 

  7. Dawson, T. C., Beck, M. A., Kuziel, W. A., Henderson, F. & Maeda, N. Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus. Am. J. Pathol. 156, 1951–1959 (2000).

    Article  CAS  Google Scholar 

  8. Coulombe, F. et al. Targeted prostaglandin E2 inhibition enhances antiviral immunity through induction of type I interferon and apoptosis in macrophages. Immunity 40, 554–568 (2014).

    Article  CAS  Google Scholar 

  9. Aldridge, J. R. Jr et al. TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection. Proc. Natl Acad. Sci. USA 106, 5306–5311 (2009).

    Article  CAS  Google Scholar 

  10. Teijaro, J. R., Walsh, K. B., Rice, S., Rosen, H. & Oldstone, M. B. Mapping the innate signaling cascade essential for cytokine storm during influenza virus infection. Proc. Natl Acad. Sci. USA 111, 3799–3804 (2014).

    Article  CAS  Google Scholar 

  11. Boring, L. et al. Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice. J. Clin. Invest 100, 2552–2561 (1997).

    Article  CAS  Google Scholar 

  12. Sato, M. et al. Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-α/β gene induction. Immunity 13, 539–548 (2000).

    Article  CAS  Google Scholar 

  13. Divangahi, M., King, I. L. & Pernet, E. Alveolar macrophages and type I IFN in airway homeostasis and immunity. Trends Immunol. 36, 307–314 (2015).

    Article  CAS  Google Scholar 

  14. Jaworska, J. et al. NLRX1 prevents mitochondrial induced apoptosis and enhances macrophage antiviral immunity by interacting with influenza virus PB1-F2 protein. Proc. Natl Acad. Sci. USA 111, E2110–E2119 (2014).

    Article  CAS  Google Scholar 

  15. Downey, J. et al. RIPK3 interacts with MAVS to regulate type I IFN-mediated immunity to influenza A virus infection. PLoS Pathog. 13, e1006326 (2017).

    Article  Google Scholar 

  16. Morita, M. et al. The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza. Cell 153, 112–125 (2013).

    Article  CAS  Google Scholar 

  17. Brandt, S. L. & Serezani, C. H. Too much of a good thing: how modulating LTB4 actions restore host defense in homeostasis or disease. Semin. Immunol. 33, 37–43 (2017).

    Article  CAS  Google Scholar 

  18. Gaudreault, E. & Gosselin, J. Leukotriene B4 induces release of antimicrobial peptides in lungs of virally infected mice. J. Immunol. 180, 6211–6221 (2008).

    Article  CAS  Google Scholar 

  19. Majer, O. et al. Type I interferons promote fatal immunopathology by regulating inflammatory monocytes and neutrophils during Candida infections. PLoS Pathog. 8, e1002811 (2012).

    Article  CAS  Google Scholar 

  20. Jenkins, S. J. et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332, 1284–1288 (2011).

    Article  CAS  Google Scholar 

  21. Robbins, C. S. et al. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat. Med. 19, 1166–1172 (2013).

    Article  CAS  Google Scholar 

  22. Bleriot, C. et al. Liver-resident macrophage necroptosis orchestrates type 1 microbicidal inflammation and type-2-mediated tissue repair during bacterial infection. Immunity 42, 145–158 (2015).

    Article  CAS  Google Scholar 

  23. Hwang, S. Y. et al. A null mutation in the gene encoding a type I interferon receptor component eliminates antiproliferative and antiviral responses to interferons alpha and beta and alters macrophage responses. Proc. Natl Acad. Sci. USA 92, 11284–11288 (1995).

    Article  CAS  Google Scholar 

  24. De Weerd, N. A. et al. Structural basis of a unique interferon-β signaling axis mediated via the receptor IFNAR1. Nat. Immunol. 14, 901–907 (2013).

    Article  CAS  Google Scholar 

  25. Gibbings, S. L. et al. Three unique interstitial macrophages in the murine lung at steady state. Am. J. Respir. Cell Mol. Biol. 57, 66–76 (2017).

    Article  CAS  Google Scholar 

  26. Jung, S. et al. Analysis of fractalkine receptor CX3CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol. Cell. Biol. 20, 4106–4114 (2000).

    Article  CAS  Google Scholar 

  27. Serezani, C. H., Lewis, C., Jancar, S. & Peters-Golden, M. Leukotriene B4 amplifies NF-κB activation in mouse macrophages by reducing SOCS1 inhibition of MyD88 expression. J. Clin. Invest. 121, 671–682 (2011).

    Article  CAS  Google Scholar 

  28. Iwasaki, A. & Pillai, P. S. Innate immunity to influenza virus infection. Nat. Rev. Immunol. 14, 315–328 (2014).

    Article  CAS  Google Scholar 

  29. Davies, L. C. et al. Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation. Nat. Commun. 4, 1886 (2013).

    Article  Google Scholar 

  30. Tang, J. et al. Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation. Sci. Adv. 1, e1400223 (2015).

    Article  Google Scholar 

  31. Yoshimura, A., Naka, T. & Kubo, M. SOCS proteins, cytokine signalling and immune regulation. Nat. Rev. Immunol. 7, 454–465 (2007).

    Article  CAS  Google Scholar 

  32. Piganis, R. A. et al. Suppressor of cytokine signaling (SOCS) 1 inhibits type I interferon (IFN) signaling via the interferon α receptor (IFNAR1)-associated tyrosine kinase Tyk2. J. Biol. Chem. 286, 33811–33818 (2011).

    Article  CAS  Google Scholar 

  33. Davidson, S., Crotta, S., McCabe, T. M. & Wack, A. Pathogenic potential of interferon αβ in acute influenza infection. Nat. Commun. 5, 3864 (2014).

    Article  CAS  Google Scholar 

  34. Channappanavar, R. et al. Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell Host Microbe 19, 181–193 (2016).

    Article  CAS  Google Scholar 

  35. De Weerd, N. A. et al. Structural basis of a unique interferon-β signaling axis mediated via the receptor IFNAR1. Nat. Immunol. 14, 901–907 (2013).

    Article  CAS  Google Scholar 

  36. Song, G., Ouyang, G. & Bao, S. The activation of Akt/PKB signaling pathway and cell survival. J. Cell. Mol. Med. 9, 59–71 (2005).

    Article  CAS  Google Scholar 

  37. Bhatt, L., Roinestad, K., Van, T. & Springman, E. B. Recent advances in clinical development of leukotriene B4 pathway drugs. Semin. Immunol. 33, 65–73 (2017).

    Article  CAS  Google Scholar 

  38. Mancuso, P., Lewis, C., Serezani, C. H., Goel, D. & Peters-Golden, M. Intrapulmonary administration of leukotriene B4 enhances pulmonary host defense against pneumococcal pneumonia. Infect. Immun. 78, 2264–2271 (2010).

    Article  CAS  Google Scholar 

  39. Mancuso, P., Nana-Sinkam, P. & Peters-Golden, M. Leukotriene B4 augments neutrophil phagocytosis of Klebsiella pneumoniae. Infect. Immun. 69, 2011–2016 (2001).

    Article  CAS  Google Scholar 

  40. Morato-Marques, M. et al. Leukotrienes target F-actin/cofilin-1 to enhance alveolar macrophage anti-fungal activity. J. Biol. Chem. 286, 28902–28913 (2011).

    Article  CAS  Google Scholar 

  41. Brandt, S. L. & Serezani, C. H. Too much of a good thing: how modulating LTB4 actions restore host defense in homeostasis or disease. Semin. Immunol. 33, 37–43 (2017).

    Article  CAS  Google Scholar 

  42. Gaush, C. R. & Smith, T. F. Replication and plaque assay of influenza virus in an established line of canine kidney cells. Appl. Microbiol. 16, 588–594 (1968).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Feoktistova, M., Geserick, P. & Leverkus, M. Crystal violet assay for determining viability of cultured cells. Cold Spring Harb. Protoc. 2016, 343–346 (2016).

    Google Scholar 

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Acknowledgements

This work was supported by a Canadian Institute of Health Research Foundation Grant (FDN-143273 to M.D.). M.D. holds a Fonds de Recherche du Québec–Santé Award and the Strauss Chair in Respiratory Diseases. E.P. is supported by a Fonds de Recherche du Québec–Santé Fellowship. J.D. is supported by the Research Institute of the McGill University Health Center. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Medicine, Meakins–Christie Laboratories, McGill International TB Centre, McGill University Health Centre, McGill University, Montreal, Quebec, Canada

    Erwan Pernet, Jeffrey Downey, Donald C. Vinh, William S. Powell & Maziar Divangahi

  2. Department of Pathology, McGill University, Montreal, Quebec, Canada

    Erwan Pernet, Jeffrey Downey & Maziar Divangahi

  3. Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada

    Erwan Pernet, Jeffrey Downey, Donald C. Vinh, William S. Powell & Maziar Divangahi

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Contributions

E.P. and M.D. conceived the project and designed the experiments. E.P. and J.D. performed the experiments. E.P., J.D. and M.D. analysed the data. W.S.P. and D.C.V. advised on the experiments. E.P. and M.D. wrote the paper. M.D. supervised the project.

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Correspondence to Maziar Divangahi.

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Pernet, E., Downey, J., Vinh, D.C. et al. Leukotriene B4–type I interferon axis regulates macrophage-mediated disease tolerance to influenza infection. Nat Microbiol 4, 1389–1400 (2019). https://doi.org/10.1038/s41564-019-0444-3

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