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* (Corresponding Author), Andrew S MacDonald* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

122 Citations (Scopus)


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 - May 2019

Bibliographical note

This research was supported by a MCCIR PhD studentship (F.R.S.), the Medical Research Council
(grant no. MR/P026907/1, H.C. and J.M.), the National Institutes of Health (grant no.
HL080396 and HL130938, C.M.E.), the Wellcome Trust Institutional Strategic Support
Fund (grant no.105610, R.K.G., D.J.T. and M.Z.K.), Medical Research Foundation
UK joint funding with Asthma UK (grant no. MRFAUK-2015–302, T.E.S.), BBSRC
studentship (C.S.), a University of Manchester Dean’s Prize Early Career Research
Fellowship (P.C.C.), Springboard Award (Academy of Medical Sciences, grant no.
SBF002/1076, P.C.C.) and MCCIR core funding (A.S.M. and T.H.). This work was also
made possible through use of the Manchester Gnotobiotic Facility that was established
with the support of the Wellcome Trust (grant no. 097820/Z/11/B), using founder mice
obtained from the Clean Mouse Facility, University of Bern, Switzerland. The Bioimaging
Facility microscopes used in this study were purchased with grants from BBSRC,
Wellcome Trust and the University of Manchester Strategic Fund.

Data Availability Statement

Data availability
The data that support the findings of this study are available from the
corresponding author upon request. RNA-seq data were deposited at Gene
Expression Omnibus, with the following accession code: GSE126309.

Code availability
Bioinformatics analyses were performed with publicly available code from


  • Immunology
  • Immunopathogenesis
  • Infection
  • Inflammation
  • Pathogenesis


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