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The transcription factor EGR2 is indispensable for tissue-specific imprinting of alveolar macrophages in health and tissue repair

View ORCID ProfileJack McCowan, View ORCID ProfilePhoebe M. Kirkwood, View ORCID ProfileFrédéric Fercoq, View ORCID ProfileWouter T’Jonck, Connar M. Mawer, Richard Cunningham, View ORCID ProfileAnanda S. Mirchandani, View ORCID ProfileAnna Hoy, View ORCID ProfileGareth-Rhys Jones, View ORCID ProfileCarsten G. Hansen, View ORCID ProfileNik Hirani, View ORCID ProfileStephen J. Jenkins, View ORCID ProfileSandrine Henri, View ORCID ProfileBernard Malissen, View ORCID ProfileSarah R. Walmsley, View ORCID ProfileDavid H. Dockrell, View ORCID ProfilePhilippa T. K. Saunders, View ORCID ProfileLeo M. Carlin, View ORCID ProfileCalum C. Bain
doi: https://doi.org/10.1101/2021.05.06.442095
Jack McCowan
1University of Edinburgh Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, EH16 4TJ, UK
2Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh BioQuarter, Edinburgh EH16 4UU, UK
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Phoebe M. Kirkwood
1University of Edinburgh Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, EH16 4TJ, UK
2Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh BioQuarter, Edinburgh EH16 4UU, UK
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Frédéric Fercoq
3Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK
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Wouter T’Jonck
1University of Edinburgh Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, EH16 4TJ, UK
2Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh BioQuarter, Edinburgh EH16 4UU, UK
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Connar M. Mawer
1University of Edinburgh Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, EH16 4TJ, UK
4Rayne Institute, University College London, 5 University St, Bloomsbury, London WC1E 6JF
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Richard Cunningham
1University of Edinburgh Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, EH16 4TJ, UK
2Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh BioQuarter, Edinburgh EH16 4UU, UK
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Ananda S. Mirchandani
1University of Edinburgh Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, EH16 4TJ, UK
2Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh BioQuarter, Edinburgh EH16 4UU, UK
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Anna Hoy
1University of Edinburgh Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, EH16 4TJ, UK
6Current address: Resolution Therapeutics Limited, Centre for Regenerative Medicine, Edinburgh BioQuarter, Edinburgh, EH16 4UU, UK
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Gareth-Rhys Jones
1University of Edinburgh Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, EH16 4TJ, UK
2Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh BioQuarter, Edinburgh EH16 4UU, UK
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Carsten G. Hansen
1University of Edinburgh Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, EH16 4TJ, UK
2Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh BioQuarter, Edinburgh EH16 4UU, UK
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Nik Hirani
1University of Edinburgh Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, EH16 4TJ, UK
2Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh BioQuarter, Edinburgh EH16 4UU, UK
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Stephen J. Jenkins
1University of Edinburgh Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, EH16 4TJ, UK
2Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh BioQuarter, Edinburgh EH16 4UU, UK
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Sandrine Henri
7Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université UM2, INSERM, U1104, CNRS UMR7280, 13288 Marseille, France
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Bernard Malissen
7Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université UM2, INSERM, U1104, CNRS UMR7280, 13288 Marseille, France
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Sarah R. Walmsley
1University of Edinburgh Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, EH16 4TJ, UK
2Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh BioQuarter, Edinburgh EH16 4UU, UK
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David H. Dockrell
1University of Edinburgh Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, EH16 4TJ, UK
2Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh BioQuarter, Edinburgh EH16 4UU, UK
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Philippa T. K. Saunders
1University of Edinburgh Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, EH16 4TJ, UK
2Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh BioQuarter, Edinburgh EH16 4UU, UK
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Leo M. Carlin
3Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK
8Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK
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Calum C. Bain
1University of Edinburgh Centre for Inflammation Research, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh BioQuarter, Edinburgh, EH16 4TJ, UK
2Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh BioQuarter, Edinburgh EH16 4UU, UK
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  • For correspondence: calum.bain@ed.ac.uk
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Abstract

Alveolar macrophages are the most abundant macrophages in the healthy lung where they play key roles in homeostasis and immune surveillance against air-borne pathogens. Tissue-specific differentiation and survival of alveolar macrophages relies on niche-derived factors, such as colony stimulating factor 2 (CSF-2) and transforming growth factor beta (TGF-β). However, the nature of the downstream molecular pathways that regulate the identity and function of alveolar macrophages and their response to injury remains poorly understood. Here, we identify that the transcriptional factor EGR2 is an evolutionarily conserved feature of lung alveolar macrophages and show that cell-intrinsic EGR2 is indispensable for the tissue-specific identity of alveolar macrophages. Mechanistically, we show that EGR2 is driven by TGF-β and CSF-2 in a PPAR-γ-dependent manner to control alveolar macrophage differentiation. Functionally, EGR2 was dispensable for lipid handling, but crucial for the effective elimination of the respiratory pathogen Streptococcus pneumoniae. Finally, we show that EGR2 is required for repopulation of the alveolar niche following sterile, bleomycin-induced lung injury and demonstrate that EGR2-dependent, monocyte-derived alveolar macrophages are vital for effective tissue repair following injury. Collectively, we demonstrate that EGR2 is an indispensable component of the transcriptional network controlling the identity and function of alveolar macrophages in health and disease.

One Sentence Summary EGR2 controls alveolar macrophage function in health and disease

Competing Interest Statement

The authors have declared no competing interest.

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The transcription factor EGR2 is indispensable for tissue-specific imprinting of alveolar macrophages in health and tissue repair
Jack McCowan, Phoebe M. Kirkwood, Frédéric Fercoq, Wouter T’Jonck, Connar M. Mawer, Richard Cunningham, Ananda S. Mirchandani, Anna Hoy, Gareth-Rhys Jones, Carsten G. Hansen, Nik Hirani, Stephen J. Jenkins, Sandrine Henri, Bernard Malissen, Sarah R. Walmsley, David H. Dockrell, Philippa T. K. Saunders, Leo M. Carlin, Calum C. Bain
bioRxiv 2021.05.06.442095; doi: https://doi.org/10.1101/2021.05.06.442095
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The transcription factor EGR2 is indispensable for tissue-specific imprinting of alveolar macrophages in health and tissue repair
Jack McCowan, Phoebe M. Kirkwood, Frédéric Fercoq, Wouter T’Jonck, Connar M. Mawer, Richard Cunningham, Ananda S. Mirchandani, Anna Hoy, Gareth-Rhys Jones, Carsten G. Hansen, Nik Hirani, Stephen J. Jenkins, Sandrine Henri, Bernard Malissen, Sarah R. Walmsley, David H. Dockrell, Philippa T. K. Saunders, Leo M. Carlin, Calum C. Bain
bioRxiv 2021.05.06.442095; doi: https://doi.org/10.1101/2021.05.06.442095

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