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

doi:10.1038/s41590-019-0352-y

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

Medical Sciences

Research output: Contribution to journal › Article › peer-review

119 Citations (Scopus)

Abstract

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 language	English
Pages (from-to)	571-580
Number of pages	10
Journal	Nature Immunology
Volume	20
Issue number	5
Early online date	1 Apr 2019
DOIs	https://doi.org/10.1038/s41590-019-0352-y
Publication status	Published - 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
bioconductor.org

Keywords

Immunology
Immunopathogenesis
Infection
Inflammation
Pathogenesis

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Cite this

Svedberg, F. R., Brown, S. L., Krauss, M. Z., Campbell, L., Sharpe, C., Clausen, M., Howell, G. J., Clark, H., Madsen, J., Evans, C. M., Sutherland, T. E., Ivens, A. C., Thornton, D. J., Grencis, R. K., Hussell, T., Cunoosamy, D. M., Cook, P. C., & MacDonald, A. S. (2019). The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation. Nature Immunology, 20(5), 571-580. https://doi.org/10.1038/s41590-019-0352-y

Svedberg, FR, Brown, SL, Krauss, MZ, Campbell, L, Sharpe, C, Clausen, M, Howell, GJ, Clark, H, Madsen, J, Evans, CM, Sutherland, TE, Ivens, AC, Thornton, DJ, Grencis, RK, Hussell, T, Cunoosamy, DM, Cook, PC & MacDonald, AS 2019, 'The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation', Nature Immunology, vol. 20, no. 5, pp. 571-580. https://doi.org/10.1038/s41590-019-0352-y

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title = "The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation",

abstract = "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.",

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

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{\textquoteright}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.",

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AU - Brown, Sheila L

AU - Krauss, Maria Z

AU - Campbell, Laura

AU - Sharpe, Catherine

AU - Clausen, Maryam

AU - Howell, Gareth J

AU - Clark, Howard

AU - Madsen, Jens

AU - Evans, Christopher M

AU - Sutherland, Tara E

AU - Ivens, Alasdair C

AU - Thornton, David J

AU - Grencis, Richard K

AU - Hussell, Tracy

AU - Cunoosamy, Danen M

AU - Cook, Peter C

AU - MacDonald, Andrew S

N1 - 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.

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N2 - 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.

AB - 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.

KW - Immunology

KW - Immunopathogenesis

KW - Infection

KW - Inflammation

KW - Pathogenesis

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DO - 10.1038/s41590-019-0352-y

M3 - Article

SN - 1529-2916

VL - 20

SP - 571

EP - 580

JO - Nature Immunology

JF - Nature Immunology

IS - 5

ER -

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

Abstract

Bibliographical note

Data Availability Statement

Keywords

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