title: Alveolar macrophage development in mice requires L-plastin for cellular localization in alveoli.
abstract: 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.Crepos-LPLfl/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 prealveolar macrophage intermediate. LPL was required for the transition from prealveolar macrophages to mature alveolar macrophages. The transition from prealveolar macrophage to alveolar macrophage requires the upregulation of the transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ), which is induced by exposure to granulocyte-macrophage colony-stimulating factor (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 2 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.
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Todd
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics.
authors.forename: Julie Y
authors.initials: JY
authors.lastname: Zhou
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics.
authors.forename: Taylor P
authors.initials: TP
authors.lastname: Szasz
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Deady
authors.affiliation: Division of Immunobiology, Department of Pathology and Immunology, and.
authors.forename: June A
authors.initials: JA
authors.lastname: D'Angelo
authors.affiliation: Division of Rehumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Cheung
authors.affiliation: Division of Rehumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Alfred H J
authors.initials: AH
authors.lastname: Kim
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics.|Division of Immunobiology, Department of Pathology and Immunology, and.
authors.forename: Sharon Celeste
authors.identifier: 0000-0001-8424-0121
authors.initials: SC
authors.lastname: Morley
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D018845:CD11 Antigens / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism*; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D011008:Pneumococcal Infections / Q000473:pathology; D000069261:Podosomes / Q000378:metabolism; D021381:Protein Transport; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018845:CD11 Antigens; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D047495:PPAR gamma; C026742:plastin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor