The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation

Freya R Svedberg, Sheila L Brown, Maria Z Krauss, Laura Campbell, Catherine Sharpe, Maryam Clausen, Gareth J Howell, Howard Clark, Jens Madsen, Christopher M Evans, Tara E Sutherland, Alasdair C Ivens, David J Thornton, Richard K Grencis, Tracy Hussell, Danen M Cunoosamy, Peter C Cook, Andrew S MacDonald

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Fine control of macrophage activation is needed to prevent inflammatory disease, particularly at barrier sites such as the lungs. However, the dominant mechanisms that regulate the activation of pulmonary macrophages during inflammation are poorly understood. We found that alveolar macrophages (AlvMs) were much less able to respond to the canonical type 2 cytokine IL-4, which underpins allergic disease and parasitic worm infections, than macrophages from lung tissue or the peritoneal cavity. We found that the hyporesponsiveness of AlvMs to IL-4 depended upon the lung environment but was independent of the host microbiota or the lung extracellular matrix components surfactant protein D (SP-D) and mucin 5b (Muc5b). AlvMs showed severely dysregulated metabolism relative to that of cavity macrophages. After removal from the lungs, AlvMs regained responsiveness to IL-4 in a glycolysis-dependent manner. Thus, impaired glycolysis in the pulmonary niche regulates AlvM responsiveness during type 2 inflammation.

Original languageEnglish
Pages (from-to)571-580
Number of pages10
JournalNature Immunology
Issue number5
Early online date1 Apr 2019
Publication statusPublished - 1 Apr 2019


  • Animals
  • Inflammation/genetics
  • Interleukin-4/genetics
  • Larva/immunology
  • Lung/immunology
  • Macrophage Activation/genetics
  • Macrophages, Alveolar/immunology
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mucin-5B/genetics
  • Nippostrongylus/immunology
  • Pulmonary Surfactant-Associated Protein D/genetics
  • Strongylida Infections/genetics

Research Beacons, Institutes and Platforms

  • Lydia Becker Institute


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