Alveolar Macrophage-expressed Plet1 is a Driver of Lung Epithelial Repair After Viral Pneumonia

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Jan 3

PMID 38167746

Authors

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 Gattenlohner

Istvan Vadasz

Rory Edward Morty

Werner Seeger

Ralph Theo Schermuly

Ana Ivonne Vazquez-Armendariz

Susanne Herold

Affiliations

Soon will be listed here.

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.

Citing Articles

Respiratory long COVID in aged hamsters features impaired lung function post-exercise with bronchiolization and fibrosis.

Heydemann L, Ciurkiewicz M, Stork T, Zdora I, Hulskotter K, Gregor K Nat Commun. 2025; 16(1):2080.

PMID: 40021627 PMC: 11871369. DOI: 10.1038/s41467-025-57267-x.

Tissue-resident immune cells: from defining characteristics to roles in diseases.

Li J, Xiao C, Li C, He J Signal Transduct Target Ther. 2025; 10(1):12.

PMID: 39820040 PMC: 11755756. DOI: 10.1038/s41392-024-02050-5.

Alveolar Macrophages in Viral Respiratory Infections: Sentinels and Saboteurs of Lung Defense.

Popperl P, Stoff M, Beineke A Int J Mol Sci. 2025; 26(1.

PMID: 39796262 PMC: 11721917. DOI: 10.3390/ijms26010407.

The immune mechanisms of acute exacerbations of idiopathic pulmonary fibrosis.

Chen T, Sun W, Xu Z Front Immunol. 2024; 15:1450688.

PMID: 39737178 PMC: 11682984. DOI: 10.3389/fimmu.2024.1450688.

Dental pulp stem cell‑derived extracellular vesicles loaded with hydrogels promote osteogenesis in rats with alveolar bone defects.

He X, Chu X, Chen X, Xiang Y, Li Z, Gao C Mol Med Rep. 2024; 31(1).

PMID: 39540371 PMC: 11582518. DOI: 10.3892/mmr.2024.13393.

References

Tighe R, Redente E, Yu Y, Herold S, Sperling A, Curtis J . Improving the Quality and Reproducibility of Flow Cytometry in the Lung. An Official American Thoracic Society Workshop Report. Am J Respir Cell Mol Biol. 2019; 61(2):150-161. PMC: 6670040. DOI: 10.1165/rcmb.2019-0191ST. View

Ghoneim H, Thomas P, McCullers J . Depletion of alveolar macrophages during influenza infection facilitates bacterial superinfections. J Immunol. 2013; 191(3):1250-9. PMC: 4907362. DOI: 10.4049/jimmunol.1300014. View

Li F, Piattini F, Pohlmeier L, Feng Q, Rehrauer H, Kopf M . Monocyte-derived alveolar macrophages autonomously determine severe outcome of respiratory viral infection. Sci Immunol. 2022; 7(73):eabj5761. DOI: 10.1126/sciimmunol.abj5761. View

Aegerter H, Kulikauskaite J, Crotta S, Patel H, Kelly G, Hessel E . Influenza-induced monocyte-derived alveolar macrophages confer prolonged antibacterial protection. Nat Immunol. 2020; 21(2):145-157. PMC: 6983324. DOI: 10.1038/s41590-019-0568-x. View

Serbina N, Pamer E . Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol. 2006; 7(3):311-7. DOI: 10.1038/ni1309. View

Murray P, Allen J, Biswas S, Fisher E, Gilroy D, Goerdt S . Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014; 41(1):14-20. PMC: 4123412. DOI: 10.1016/j.immuni.2014.06.008. View

Herold S, Mayer K, Lohmeyer J . Acute lung injury: how macrophages orchestrate resolution of inflammation and tissue repair. Front Immunol. 2012; 2:65. PMC: 3342347. DOI: 10.3389/fimmu.2011.00065. View

Herold S, Steinmueller M, von Wulffen W, Cakarova L, Pinto R, Pleschka S . Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand. J Exp Med. 2008; 205(13):3065-77. PMC: 2605231. DOI: 10.1084/jem.20080201. View

Merad M, Martin J . Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020; 20(6):355-362. PMC: 7201395. DOI: 10.1038/s41577-020-0331-4. View

10.

Wendisch D, Dietrich O, Mari T, von Stillfried S, Ibarra I, Mittermaier M . SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis. Cell. 2021; 184(26):6243-6261.e27. PMC: 8626230. DOI: 10.1016/j.cell.2021.11.033. View

11.

Peteranderl C, Morales-Nebreda L, Selvakumar B, Lecuona E, Vadasz I, Morty R . Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection. J Clin Invest. 2016; 126(4):1566-80. PMC: 4811131. DOI: 10.1172/JCI83931. View

12.

Lucas C, Medina C, Bruton F, Dorward D, Raymond M, Tufan T . Pannexin 1 drives efficient epithelial repair after tissue injury. Sci Immunol. 2022; 7(71):eabm4032. PMC: 7612772. DOI: 10.1126/sciimmunol.abm4032. View

13.

Dagher R, Copenhaver A, Besnard V, Berlin A, Hamidi F, Maret M . IL-33-ST2 axis regulates myeloid cell differentiation and activation enabling effective club cell regeneration. Nat Commun. 2020; 11(1):4786. PMC: 7508874. DOI: 10.1038/s41467-020-18466-w. View

14.

Lechner A, Driver I, Lee J, Conroy C, Nagle A, Locksley R . Recruited Monocytes and Type 2 Immunity Promote Lung Regeneration following Pneumonectomy. Cell Stem Cell. 2017; 21(1):120-134.e7. PMC: 5501755. DOI: 10.1016/j.stem.2017.03.024. View

15.

Depreter M, Blair N, Gaskell T, Nowell C, Davern K, Pagliocca A . Identification of Plet-1 as a specific marker of early thymic epithelial progenitor cells. Proc Natl Acad Sci U S A. 2008; 105(3):961-6. PMC: 2242700. DOI: 10.1073/pnas.0711170105. View

16.

Murray A, Sienerth A, Hemberger M . Plet1 is an epigenetically regulated cell surface protein that provides essential cues to direct trophoblast stem cell differentiation. Sci Rep. 2016; 6:25112. PMC: 4848516. DOI: 10.1038/srep25112. View

17.

Nijhof J, Braun K, Giangreco A, van Pelt C, Kawamoto H, Boyd R . The cell-surface marker MTS24 identifies a novel population of follicular keratinocytes with characteristics of progenitor cells. Development. 2006; 133(15):3027-37. DOI: 10.1242/dev.02443. View

18.

Bennett A, Farley A, Blair N, Gordon J, Sharp L, Blackburn C . Identification and characterization of thymic epithelial progenitor cells. Immunity. 2002; 16(6):803-14. DOI: 10.1016/s1074-7613(02)00321-7. View

19.

Ulyanchenko S, ONeill K, Medley T, Farley A, Vaidya H, Cook A . Identification of a Bipotent Epithelial Progenitor Population in the Adult Thymus. Cell Rep. 2016; 14(12):2819-32. PMC: 4819909. DOI: 10.1016/j.celrep.2016.02.080. View

20.

Raymond K, Richter A, Kreft M, Frijns E, Janssen H, Slijper M . Expression of the orphan protein Plet-1 during trichilemmal differentiation of anagen hair follicles. J Invest Dermatol. 2010; 130(6):1500-13. DOI: 10.1038/jid.2010.4. View