Alveolar macrophage-expressed Plet1 is a driver of lung epithelial repair after viral pneumonia. Influenza A virus (IAV) infection mobilizes bone marrow-derived macrophages (BMDM) that gradually transition to tissue-resident alveolar macrophages (TR-AM) in the inflamed lung. Using high-dimensional single-cell transcriptomics, complex lung organoid modeling, in vivo adoptive cell transfer, and BMDM-specific gene targeting, the study found that transitioning BMDM and TR-AM highly express Plet1. Plet1 is released from alveolar macrophages and acts as an important mediator of macrophage-epithelial cross-talk during lung repair by inducing proliferation of alveolar epithelial cells and re-sealing 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. Tissue-resident alveolar macrophages (TR-AM) are long-lived cells localized to the alveolar space, where they exert key functions in maintaining tissue homeostasis and in immediate host defense. During viral pneumonia, TR-AM are depleted and gradually replaced by BMDM, which undergo a transition to tissue-regenerative macrophages. Plet1 is expressed in proliferating epithelia and in stem cell niches, and is involved in keratinocyte migration and gut epithelial wound healing. The study reveals that during the resolution phase of viral pneumonia, a transitional subpopulation of BMDM and the re-emerging TR-AM pool constitute key components of epithelial stem/progenitor cell niches and contribute to lung regeneration through Plet1 expression. Plet1-expressing macrophages efficiently attenuate IAV-induced epithelial injury and foster stem/progenitor cell-driven alveolarization and barrier repair. Intraalveolar administration of recombinant Plet1 rescued mice from fatal viral pneumonia, highlighting its potential as a therapeutic to combat severe inflammatory lung injury in viral pneumonia. Plet1 is a GPI-anchored membrane protein that drives epithelial repair by inducing proliferation of alveolar epithelial cells and re-sealing the epithelial barrier. Plet1-expressing macrophages support alveolar epithelial cell proliferation and barrier function, and its expression is crucial for lung tissue recovery and survival after severe viral infection. Orotracheal administration of rPlet1 rescued mice after lethal IAV infection, suggesting its potential as a treatment strategy for human virus-induced ARDS.Alveolar macrophage-expressed Plet1 is a driver of lung epithelial repair after viral pneumonia. Influenza A virus (IAV) infection mobilizes bone marrow-derived macrophages (BMDM) that gradually transition to tissue-resident alveolar macrophages (TR-AM) in the inflamed lung. Using high-dimensional single-cell transcriptomics, complex lung organoid modeling, in vivo adoptive cell transfer, and BMDM-specific gene targeting, the study found that transitioning BMDM and TR-AM highly express Plet1. Plet1 is released from alveolar macrophages and acts as an important mediator of macrophage-epithelial cross-talk during lung repair by inducing proliferation of alveolar epithelial cells and re-sealing 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. Tissue-resident alveolar macrophages (TR-AM) are long-lived cells localized to the alveolar space, where they exert key functions in maintaining tissue homeostasis and in immediate host defense. During viral pneumonia, TR-AM are depleted and gradually replaced by BMDM, which undergo a transition to tissue-regenerative macrophages. Plet1 is expressed in proliferating epithelia and in stem cell niches, and is involved in keratinocyte migration and gut epithelial wound healing. The study reveals that during the resolution phase of viral pneumonia, a transitional subpopulation of BMDM and the re-emerging TR-AM pool constitute key components of epithelial stem/progenitor cell niches and contribute to lung regeneration through Plet1 expression. Plet1-expressing macrophages efficiently attenuate IAV-induced epithelial injury and foster stem/progenitor cell-driven alveolarization and barrier repair. Intraalveolar administration of recombinant Plet1 rescued mice from fatal viral pneumonia, highlighting its potential as a therapeutic to combat severe inflammatory lung injury in viral pneumonia. Plet1 is a GPI-anchored membrane protein that drives epithelial repair by inducing proliferation of alveolar epithelial cells and re-sealing the epithelial barrier. Plet1-expressing macrophages support alveolar epithelial cell proliferation and barrier function, and its expression is crucial for lung tissue recovery and survival after severe viral infection. Orotracheal administration of rPlet1 rescued mice after lethal IAV infection, suggesting its potential as a treatment strategy for human virus-induced ARDS.