Alveolar macrophage development in mice requires L-plastin for cellular localization and retention within alveoli.

Alveolar macrophages are lung-resident sentinel cells that develop perinatally and protect against pulmonary infection. Molecular mechanisms controlling alveolar macrophage generation have not been fully defined. Here we show that the actin-bundling protein L-plastin (LPL) is required for the perinatal development of alveolar macrophages. Mice expressing a conditional allele of LPL (CD11c.Cre pos -LPL fl/fl ) exhibited significant reductions in alveolar macrophages and failed to effectively clear pulmonary pneumococcal infection, showing that immunodeficiency results from reduced alveolar macrophage numbers. We next identified the phase of alveolar macrophage development requiring LPL. In mice, fetal monocytes arrive in the lungs during a late fetal stage, maturing to alveolar macrophages through a pre-alveolar macrophage intermediate. LPL was required for the transition from pre-alveolar macrophages to mature alveolar macrophages. The transition from pre-alveolar macrophage to alveolar macrophage requires the upregulation of the transcription factor PPAR-γ which is induced by exposure to GM-CSF. Despite abundant lung GM-CSF and intact GM-CSF receptor signaling, PPAR-γ was not sufficiently upregulated in developing alveolar macrophages in LPL -/- pups, suggesting that precursor cells were not correctly localized to the alveoli, where GM-CSF is produced. We found that LPL supports two actin-based processes essential for correct localization of alveolar macrophage precursors: 1) transmigration into the alveoli, and 2) engraftment in the alveoli. We thus identify a molecular pathway governing neonatal alveolar macrophage development, and show that genetic disruption of alveolar macrophage development results in immunodeficiency.