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

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.

Data availability

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

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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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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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