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, Andrew S MacDonald

Medical Sciences

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

100 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
DOIs	https://doi.org/10.1038/s41590-019-0352-y
Publication status	Published - 1 Apr 2019

Keywords

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

Access to Document

10.1038/s41590-019-0352-y

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

@article{ce829fde92cc4202ab945479a2a595ca,

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.",

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

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}",

year = "2019",

month = apr,

day = "1",

doi = "10.1038/s41590-019-0352-y",

language = "English",

volume = "20",

pages = "571--580",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Publishing Group",

number = "5",

}

TY - JOUR

T1 - The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation

AU - Svedberg, Freya R

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

PY - 2019/4/1

Y1 - 2019/4/1

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 - Animals

KW - Inflammation/genetics

KW - Interleukin-4/genetics

KW - Larva/immunology

KW - Lung/immunology

KW - Macrophage Activation/genetics

KW - Macrophages

KW - Alveolar/immunology

KW - Mice

KW - Inbred BALB C

KW - Inbred C57BL

KW - Knockout

KW - Transgenic

KW - Mucin-5B/genetics

KW - Nippostrongylus/immunology

KW - Pulmonary Surfactant-Associated Protein D/genetics

KW - Strongylida Infections/genetics

U2 - 10.1038/s41590-019-0352-y

DO - 10.1038/s41590-019-0352-y

M3 - Article

VL - 20

SP - 571

EP - 580

JO - Nature Immunology

JF - Nature Immunology

SN - 1529-2908

IS - 5

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this