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.
- Pervizaj-Oruqaj, L.
- Selvakumar, B.
- Ferrero, M. R.
- Heiner, M.
- Malainou, C.
- Glaser, R. D.
- Wilhelm, J.
- Bartkuhn, M.
- Weiss, A.
- Alexopoulos, I.
- Witte, B.
- Gattenlöhner, S.
- Vadász, I.
- Morty, R. E.
- Seeger, W.
- Schermuly, R. T.
- Vazquez-Armendariz, A. I.
- Herold, S.
Keywords
- Animals
- Female
- Humans
- Mice
- Pregnancy
- *Influenza A virus
- *Influenza, Human
- Lung
- Macrophages, Alveolar
- Placenta
- *Pneumonia, Viral
