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

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. Leukotriene B4 signalling contributes to disease tolerance to influenza virus infection by stimulating the production of interferon-α (IFN-α) by interstitial macrophages. IFN-α, in turn, suppresses in situ inflammatory, monocyte-derived macrophage proliferation and mitigates lung immunopathology.