Alveolar macrophage-expressed Plet1 is a driver of lung epithelial repair after viral pneumonia

Learta Pervizaj-Oruqaj; Balachandar Selvakumar; Maximiliano Ruben Ferrero; Monika Heiner; Christina Malainou; Rolf David Glaser; Jochen Wilhelm; Marek Bartkuhn; Astrid Weiss; Ioannis Alexopoulos; Biruta Witte; Stefan Gattenlöhner; István Vadász; Rory Edward Morty; Werner Seeger; Ralph Theo Schermuly; Ana Ivonne Vazquez-Armendariz; Susanne Herold

doi:10.1038/s41467-023-44421-6

Alveolar macrophage-expressed Plet1 is a driver of lung epithelial repair after viral pneumonia

Nat Commun. 2024 Jan 2;15(1):87. doi: 10.1038/s41467-023-44421-6.

Authors

Learta Pervizaj-Oruqaj^#^{1

2

3}, Balachandar Selvakumar^#^{1

4

5}, Maximiliano Ruben Ferrero^#^{1

2

3

4

5}, Monika Heiner^{1

2

3}, Christina Malainou^{1

2

3}, Rolf David Glaser^{2

6}, Jochen Wilhelm^{2

3

7}, Marek Bartkuhn^{2

6}, Astrid Weiss^{3

7}, Ioannis Alexopoulos^{1

2

3}, Biruta Witte⁸, Stefan Gattenlöhner⁹, István Vadász^{2

3

7}, Rory Edward Morty¹⁰, Werner Seeger^{2

3

4

5

7}, Ralph Theo Schermuly^{2

3

7}, Ana Ivonne Vazquez-Armendariz^{1

2

3

11}, Susanne Herold^{12

13

14}

Affiliations

¹ Department of Internal Medicine V, Universities of Giessen and Marburg Lung Center, University Hospital Giessen, Justus Liebig University, Member of the German Center for Lung Research (DZL), Giessen, Germany.
² Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany.
³ Excellence Cluster Cardio-Pulmonary Institute (CPI), Giessen, Germany.
⁴ Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
⁵ Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA), Buenos Aires, Argentina.
⁶ Biomedical Informatics and Systems Medicine, Justus Liebig University, Giessen, Germany.
⁷ Department of Internal Medicine II, Universities of Giessen and Marburg Lung Center, University Hospital Giessen, Justus Liebig University, Member of the German Center for Lung Research (DZL), Giessen, Germany.
⁸ Department of General and Thoracic Surgery, University Hospital of Giessen, Giessen, Germany.
⁹ Department of Pathology, University Hospital of Giessen, Giessen, Germany.
¹⁰ Department of Translational Pulmonology and the Translational Lung Research Center, University Hospital Heidelberg, Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
¹¹ University of Bonn, Transdisciplinary Research Area Life and Health, Organoid Biology, Life & Medical Sciences Institute, Bonn, Germany.
¹² Department of Internal Medicine V, Universities of Giessen and Marburg Lung Center, University Hospital Giessen, Justus Liebig University, Member of the German Center for Lung Research (DZL), Giessen, Germany. Susanne.herold@innere.med.uni-giessen.de.
¹³ Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany. Susanne.herold@innere.med.uni-giessen.de.
¹⁴ Excellence Cluster Cardio-Pulmonary Institute (CPI), Giessen, Germany. Susanne.herold@innere.med.uni-giessen.de.

^# Contributed equally.

Abstract

Influenza A virus (IAV) infection mobilizes bone marrow-derived macrophages (BMDM) that gradually undergo transition to tissue-resident alveolar macrophages (TR-AM) in the inflamed lung. Combining high-dimensional single-cell transcriptomics with complex lung organoid modeling, in vivo adoptive cell transfer, and BMDM-specific gene targeting, we found that transitioning ("regenerative") BMDM and TR-AM highly express Placenta-expressed transcript 1 (Plet1). We reveal that Plet1 is released from alveolar macrophages, and acts as important mediator of macrophage-epithelial cross-talk during lung repair by inducing proliferation of alveolar epithelial cells and re-sealing of the epithelial barrier. Intratracheal administration of recombinant Plet1 early in the disease course attenuated viral lung injury and rescued mice from otherwise fatal disease, highlighting its therapeutic potential.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Female
Humans
Influenza A virus*
Influenza, Human*
Lung
Macrophages, Alveolar
Mice
Placenta
Pneumonia, Viral*
Pregnancy

Substances

Plet-1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding