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

The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation
The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation
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.
Immunology, macrophage, Inflammation, il-4
1529-2908
571-580
Svedberg, Freya R.
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Brown, Sheila L.
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Krauss, Maria Z.
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Campbell, Laura
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Sharpe, Catherine
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Clausen, Maryam
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Howell, Gareth J.
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Clark, Howard
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Madsen, Jens
b5d8ae35-00ac-4d19-930e-d8ddec497359
Evans, Christopher M.
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Sutherland, Tara E.
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Ivens, Alasdair C.
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Thornton, David J.
a8e0a592-11d6-4e59-a8b9-27eafea3e805
Grencis, Richard K.
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Hussell, Tracy
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Cunoosamy, Danen M.
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Cook, Peter C.
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MacDonald, Andrew S.
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Svedberg, Freya R.
4236e41e-9fd7-4a4d-962f-a61eccc9da4e
Brown, Sheila L.
0b0bfa9d-2f7f-4763-aa72-6add50bcda5e
Krauss, Maria Z.
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Campbell, Laura
5c7a9779-c58d-4bc6-993e-89b791fc5165
Sharpe, Catherine
0ee0762a-5e1c-4145-9fa8-b184f58c66c2
Clausen, Maryam
2c8677bf-a611-43c8-b807-eb68e8b36f7f
Howell, Gareth J.
d0034299-daf8-404f-b2be-0843d9cedf10
Clark, Howard
70550b6d-3bd7-47c6-8c02-4f43f37d5213
Madsen, Jens
b5d8ae35-00ac-4d19-930e-d8ddec497359
Evans, Christopher M.
f10b48d5-078b-4540-aee0-d6c058518b96
Sutherland, Tara E.
785b5a23-99ec-4d60-b86f-e4e13ad08945
Ivens, Alasdair C.
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Thornton, David J.
a8e0a592-11d6-4e59-a8b9-27eafea3e805
Grencis, Richard K.
d510326b-f979-450d-b063-cefe20393ee2
Hussell, Tracy
21fcf12c-50db-4b50-98c8-0f75c91ec29c
Cunoosamy, Danen M.
558f8953-1d0e-4232-a7c5-b350f9679d70
Cook, Peter C.
4ddbdf79-cc25-4c2a-b6d8-6404e037b9b6
MacDonald, Andrew S.
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Svedberg, Freya R., Brown, Sheila L., Krauss, Maria Z., Campbell, Laura, Sharpe, Catherine, Clausen, Maryam, Howell, Gareth J., Clark, Howard, Madsen, Jens, Evans, Christopher M., Sutherland, Tara E., Ivens, Alasdair C., Thornton, David J., Grencis, Richard K., Hussell, Tracy, Cunoosamy, Danen M., Cook, Peter C. and MacDonald, Andrew S. (2019) The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation. Nature Immunology, 20, 571-580. (doi:10.1038/s41590-019-0352-y).

Record type: Article

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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Cook et al 2018_merged_final - Accepted Manuscript
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Accepted/In Press date: 14 February 2019
Published date: 1 April 2019
Keywords: Immunology, macrophage, Inflammation, il-4

Identifiers

Local EPrints ID: 430653
URI: http://eprints.soton.ac.uk/id/eprint/430653
ISSN: 1529-2908
PURE UUID: 308577f9-3110-4061-9a0a-9bbc5ed080c3
ORCID for Jens Madsen: ORCID iD orcid.org/0000-0003-1664-7645

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Date deposited: 07 May 2019 16:30
Last modified: 10 Jan 2022 05:24

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Contributors

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

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