Decipher immune response in early recovery phase of respiratory virus-induced disorder [Ly6GMacs scRNA-seq]
Appropriate lung repair responses are essential to restore functional integrity and prevent severe disease phenotypes after injury. While macrophages are thought to contribute to repair, whether distinct subsets occupy particular niches and assume dedicated tasks to mediate host recovery post- injury remains unknown. Using an in vivo model of influenza A virus (IAV) infection in combination with single-cell and spatial transcriptomic analyses, bone marrow chimeras and monocyte fate-mapping, we found the transitional appearance of Ccr2-dependent monocyte-derived Ly6G+ macrophages (Ly6G Macs) after viral clearance. Ly6G Macs inhabited the alveolar spaces of regenerating perilesional areas, exhibited a unique ultrastructural morphology as well as a high metabolic potential. Using in vivo gene targeting and ex vivo wound healing assays, we found that Ly6G Macs could limit disease severity and promote alveolar regeneration via interleukin-4 receptor- and arginase-1-dependent mechanisms acting on type 2 alveolar epithelial cells. We also found evidence that similar macrophages existed in other models of lung injury and in the airways of virally-infected humans. Our study thus identifies perilesional alveolar Ly6G Macs as a spatially-restricted short-lived macrophage subset engaging a crosstalk with type 2 alveolar epithelial cells to promote alveolar regeneration and recovery post-injury, thus representing an attractive therapeutic target. Overall design: To investigate the role of myeloid cells in early recovery phase of respiratory virus-induced disorders we used a clinically relevant model of flu (H1N1 PR8 strain) and analysed immune cell populations 10 days post infection, when virus is completely cleared from the lung. Live CD45+, F4/80 and/or CD11b cells were FACS-sorted and their gene expression profile was analysed by RNA-seq.