Recruited Monocytes and Type 2 Immunity Promote Lung Regeneration following Pneumonectomy

Highlights

• Single-cell RNA-seq reveals myeloid cell heterogeneity in the regenerating lung

• CCR2+ myeloid cells and Il4ra signaling are required for lung regeneration

• Monocytes and macrophages modulate type 2 alveolar stem cell behaviors

• ILC2s are a source of IL-13 in the regenerating lung

Summary

To investigate the role of immune cells in lung regeneration, we used a unilateral pneumonectomy model that promotes the formation of new alveoli in the remaining lobes. Immunofluorescence and single-cell RNA sequencing found CD115+ and CCR2+ monocytes and M2-like macrophages accumulating in the lung during the peak of type 2 alveolar epithelial stem cell (AEC2) proliferation. Genetic loss of function in mice and adoptive transfer studies revealed that bone marrow-derived macrophages (BMDMs) traffic to the lung through a CCL2-CCR2 chemokine axis and are required for optimal lung regeneration, along with Il4ra-expressing leukocytes. Our data suggest that these cells modulate AEC2 proliferation and differentiation. Finally, we provide evidence that group 2 innate lymphoid cells are a source of IL-13, which promotes lung regeneration. Together, our data highlight the potential for immunomodulatory therapies to stimulate alveologenesis in adults.