Defective monocyte motility disrupts alveolar macrophage development in mice deficient for L-plastin

Abstract

Abstract Alveolar macrophages, sentinel cells essential to pulmonary immunity, mature during perinatal development. Fetal monocytes arrive in the lungs during late embryonic development and mature into alveolar macrophages through a pre-alveolar macrophage intermediate. Here we identify a requirement for the actin-bundling protein L-plastin (LPL) in a key transition during neonatal alveolar macrophage development. LPL−/− mice demonstrated a two-fold reduction in alveolar macrophages. The requirement for LPL was cell-intrinsic, as mice expressing a CD11c-specific deletion of LPL (CD11c.Cre-LPLfl/fl mice) also exhibited a significant (> 75%) reduction in alveolar macrophages. Impaired alveolar macrophage development in LPL−/− mice resulted from a block in the transition of the intermediate pre-alveolar macrophages to mature alveolar macrophages. Differentiation of monocytes into alveolar macrophages requires transit to the alveolar space, which exposes precursor cells to the essential growth factor GM-CSF, which in turn upregulates the transcription factor PPAR-γ. LPL is required for monocyte migration into the alveoli, providing a mechanism by which LPL deficiency impairs alveolar macrophage maturation. As predicted by this model, pre-alveolar macrophages in LPL−/− mice did not upregulate PPAR-γ, indicating that exposure to GM-CSF is reduced. Finally, LPL−/−, CD11c.Cre-LPLfl/fl and CD11c.Cre-LPLfl/+ mice failed to efficiently clear pulmonary pneumococcal infection, revealing a physiological consequence of impaired alveolar macrophage development. In summary, we show that genetic disruption of monocyte motility can impair differentiation of a key cell type, subsequently impairing host immunity.