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Chronic pharmacological antagonism of the GM-CSF receptor in mice does not replicate the pulmonary alveolar proteinosis phenotype but does alter lung surfactant turnover

Chronic pharmacological antagonism of the GM-CSF receptor in mice does not replicate the pulmonary alveolar proteinosis phenotype but does alter lung surfactant turnover
Chronic pharmacological antagonism of the GM-CSF receptor in mice does not replicate the pulmonary alveolar proteinosis phenotype but does alter lung surfactant turnover

Granulocyte macrophage colony stimulating factor (GM-CSF) is a key participant in, and a clinical target for, the treatment of inflammatory diseases including rheumatoid arthritis (RA). Therapeutic inhibition of GM-CSF signalling using monoclonal antibodies to the α-subunit of the GM-CSF receptor (GMCSFRα) has shown clear benefit in patients with RA, giant cell arteritis (GCAs) and some efficacy in severe SARS-CoV-2 infection. However, GM-CSF autoantibodies are associated with the development of pulmonary alveolar proteinosis (PAP), a rare lung disease characterised by alveolar macrophage (AM) dysfunction and the accumulation of surfactant lipids. We assessed how the anti-GMCSFRα approach might impact surfactant turnover in the airway. Female C57BL/6J mice received a mouse-GMCSFRα blocking antibody (CAM-3003) twice per week for up to 24 weeks. A parallel, comparator cohort of the mouse PAP model, GM-CSF receptor β subunit (GMCSFRβ) knock-out (KO), was maintained up to 16 weeks. We assessed lung tissue histopathology alongside lung phosphatidylcholine (PC) metabolism using stable isotope lipidomics. GMCSFRβ KO mice reproduced the histopathological and biochemical features of PAP, accumulating surfactant PC in both broncho-alveolar lavage fluid (BALF) and lavaged lung tissue. The incorporation pattern of methyl-D 9-choline showed impaired catabolism and not enhanced synthesis. In contrast, chronic supra-pharmacological CAM-3003 exposure (100 mg/kg) over 24 weeks did not elicit a histopathological PAP phenotype despite some changes in lung PC catabolism. Lack of significant impairment of AM catabolic function supports clinical observations that therapeutic antibodies to this pathway have not been associated with PAP in clinical trials.

alveolar surfactant, Lipidomics, GM-CSF, rheumatoid arthritis, SARS-CoV-2, Giant Cell Arteritis, alveolar lipoproteinosis
0143-5221
2559-2573
Corkhill, Dominic
04aed460-e019-455a-9661-9089333cff68
Hunt, Alan
95a3e223-da96-40e7-b47d-27dce014e305
Hinrichs, Mary Jane
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White, Nicholas
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Rebelatto, Marlon
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Roskos, Lorin
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Nys, Josquin
b3299db8-899a-496f-a8c7-f22edae1e107
Scott, Alison
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Robinson, Matthew
9bd2fe51-1df4-4313-be1c-b71e1494d154
Ryan, Patricia
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Postle, Anthony
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Sleeman, Matthew
80e3b85a-17c5-45ee-a477-5a73d46660d0
Corkhill, Dominic
04aed460-e019-455a-9661-9089333cff68
Hunt, Alan
95a3e223-da96-40e7-b47d-27dce014e305
Hinrichs, Mary Jane
a91fcff9-ae05-4cfa-9d1a-cfb49236875f
White, Nicholas
122b810d-8001-4771-93af-bad259efa76e
Rebelatto, Marlon
1232c0f9-791f-464a-a616-bc6a54b5af2c
Roskos, Lorin
8eec3056-97e2-40ea-b835-3678cfed547a
Nys, Josquin
b3299db8-899a-496f-a8c7-f22edae1e107
Scott, Alison
d92dc2e1-5c8a-405b-a975-ab015fbac46a
Robinson, Matthew
9bd2fe51-1df4-4313-be1c-b71e1494d154
Ryan, Patricia
61e33a04-d87b-4f6c-9672-b4bf77a55901
Postle, Anthony
0fa17988-b4a0-4cdc-819a-9ae15c5dad66
Sleeman, Matthew
80e3b85a-17c5-45ee-a477-5a73d46660d0

Corkhill, Dominic, Hunt, Alan, Hinrichs, Mary Jane, White, Nicholas, Rebelatto, Marlon, Roskos, Lorin, Nys, Josquin, Scott, Alison, Robinson, Matthew, Ryan, Patricia, Postle, Anthony and Sleeman, Matthew (2021) Chronic pharmacological antagonism of the GM-CSF receptor in mice does not replicate the pulmonary alveolar proteinosis phenotype but does alter lung surfactant turnover. Clinical Science, 135 (22), 2559-2573, [CS20210713]. (doi:10.1042/CS20210713).

Record type: Article

Abstract

Granulocyte macrophage colony stimulating factor (GM-CSF) is a key participant in, and a clinical target for, the treatment of inflammatory diseases including rheumatoid arthritis (RA). Therapeutic inhibition of GM-CSF signalling using monoclonal antibodies to the α-subunit of the GM-CSF receptor (GMCSFRα) has shown clear benefit in patients with RA, giant cell arteritis (GCAs) and some efficacy in severe SARS-CoV-2 infection. However, GM-CSF autoantibodies are associated with the development of pulmonary alveolar proteinosis (PAP), a rare lung disease characterised by alveolar macrophage (AM) dysfunction and the accumulation of surfactant lipids. We assessed how the anti-GMCSFRα approach might impact surfactant turnover in the airway. Female C57BL/6J mice received a mouse-GMCSFRα blocking antibody (CAM-3003) twice per week for up to 24 weeks. A parallel, comparator cohort of the mouse PAP model, GM-CSF receptor β subunit (GMCSFRβ) knock-out (KO), was maintained up to 16 weeks. We assessed lung tissue histopathology alongside lung phosphatidylcholine (PC) metabolism using stable isotope lipidomics. GMCSFRβ KO mice reproduced the histopathological and biochemical features of PAP, accumulating surfactant PC in both broncho-alveolar lavage fluid (BALF) and lavaged lung tissue. The incorporation pattern of methyl-D 9-choline showed impaired catabolism and not enhanced synthesis. In contrast, chronic supra-pharmacological CAM-3003 exposure (100 mg/kg) over 24 weeks did not elicit a histopathological PAP phenotype despite some changes in lung PC catabolism. Lack of significant impairment of AM catabolic function supports clinical observations that therapeutic antibodies to this pathway have not been associated with PAP in clinical trials.

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Accepted/In Press date: 12 November 2021
e-pub ahead of print date: 26 November 2021
Published date: November 2021
Keywords: alveolar surfactant, Lipidomics, GM-CSF, rheumatoid arthritis, SARS-CoV-2, Giant Cell Arteritis, alveolar lipoproteinosis

Identifiers

Local EPrints ID: 452362
URI: http://eprints.soton.ac.uk/id/eprint/452362
ISSN: 0143-5221
PURE UUID: 42d4931e-5561-42fb-927d-d86ea07e4ec5
ORCID for Alan Hunt: ORCID iD orcid.org/0000-0001-5938-2152
ORCID for Anthony Postle: ORCID iD orcid.org/0000-0001-7361-0756

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Date deposited: 08 Dec 2021 18:47
Last modified: 06 Jun 2024 04:09

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Contributors

Author: Dominic Corkhill
Author: Alan Hunt ORCID iD
Author: Mary Jane Hinrichs
Author: Nicholas White
Author: Marlon Rebelatto
Author: Lorin Roskos
Author: Josquin Nys
Author: Alison Scott
Author: Matthew Robinson
Author: Patricia Ryan
Author: Anthony Postle ORCID iD
Author: Matthew Sleeman

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