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Nat Microbiol. 2019 Aug;4(8):1389-1400. doi: 10.1038/s41564-019-0444-3. Epub 2019 May 20.

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

Pernet E1,2,3, Downey J1,2,3, Vinh DC1,3, Powell WS1,3, Divangahi M4,5,6.

Author information

1
Department of Medicine, Meakins-Christie Laboratories, McGill International TB Centre, McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
2
Department of Pathology, McGill University, Montreal, Quebec, Canada.
3
Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
4
Department of Medicine, Meakins-Christie Laboratories, McGill International TB Centre, McGill University Health Centre, McGill University, Montreal, Quebec, Canada. maziar.divangahi@mcgill.ca.
5
Department of Pathology, McGill University, Montreal, Quebec, Canada. maziar.divangahi@mcgill.ca.
6
Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada. maziar.divangahi@mcgill.ca.

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.

PMID:
31110361
DOI:
10.1038/s41564-019-0444-3

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