Abstract
Macrophages are critical to organ structure and function in health and disease. To determine mechanisms by which granulocyte/macrophage-colony stimulating factor (GM-CSF) signaling normally maintains surfactant homeostasis and how its disruption causes pulmonary alveolar proteinosis (PAP), we evaluated lipid composition in alveolar macrophages and lung surfactant, macrophage-mediated surfactant clearance kinetics/dynamics, and cholesterol-targeted pharmacotherapy of PAP in vitro and in vivo. Without GM-CSF signaling, surfactant-exposed macrophages massively accumulated cholesterol ester-rich lipid-droplets and surfactant had an increased proportion of cholesterol. GM-CSF regulated cholesterol clearance in macrophages in constitutive, dose-dependent, and reversible fashion but did not affect phospholipid clearance. PPARγ-agonist therapy increased cholesterol clearance in macrophages and reduced disease severity in PAP mice. Results demonstrate that GM-CSF is required for cholesterol clearance in macrophages, identify reduced cholesterol clearance as the primary macrophage defect driving PAP pathogenesis, and support the feasibility of translating pioglitazone as a novel pharmacotherapy of PAP.
Highlights
granulocyte/macrophage-colony stimulating factor (GM-CSF) has emerged as an important regulator of the ontogeny, renewal, and functions of macrophages in health and disease, in the lung[1,2,3,4]
We characterized the lipids accumulating in alveolar macrophages in pulmonary alveolar proteinosis (PAP) since the earliest cellular abnormality following disruption of GM-CSF signaling is the development of foamy alveolar macrophages enlarged by accumulation of intracytoplasmic lipid droplets[9]
Compared to age-matched WT controls, the total cholesterol level in alveolar macrophages from Csf2−/− mice was increased 2.9-fold at six weeks, rose further to 5.4-fold at 12 weeks, plateaued at 5-fold at 24 weeks (Fig. 1f), and was increased in both Csf2−/− and Csf2rb−/− mice (Fig. 1g). These results indicate that esterified and free cholesterol are the predominant lipid species accumulating in alveolar macrophages in PAP mice, GM-CSF regulation of cholesterol clearance is not limited to alveolar macrophages but is common to other macrophage populations, and accumulation of cholesterol is not an intrinsic defect caused by GM-CSF deficiency but requires exposure to surfactant
Summary
Anthony Sallese[1,2,3], Takuji Suzuki[1,2], Cormac McCarthy[1,2,4,5], James Bridges[2], Alyssa Filuta[2], Paritha Arumugam[1,2], Kenjiro Shima[1,2], Yan Ma1,2, Matthew Wessendarp[1,2], Diane Black[1,2], Claudia Chalk[1,2], Brenna Carey1,2 & Bruce C. To determine mechanisms by which granulocyte/macrophage-colony stimulating factor (GM-CSF) signaling normally maintains surfactant homeostasis and how its disruption causes pulmonary alveolar proteinosis (PAP), we evaluated lipid composition in alveolar macrophages and lung surfactant, macrophage-mediated surfactant clearance kinetics/dynamics, and cholesterol-targeted pharmacotherapy of PAP in vitro and in vivo. PPARγ-agonist therapy increased cholesterol clearance in macrophages and reduced disease severity in PAP mice. Pulmonary alveolar macrophages require GM-CSF to maintain surfactant homeostasis, which is critical to alveolar stability and lung function[5, 6], and disruption of GM-CSF signaling causes pulmonary alveolar proteinosis (PAP) – a syndrome of progressive alveolar surfactant accumulation and resulting hypoxemic respiratory failure that occurs in men, women and children[3, 7]. PPARγ- or LXR-agonist mediated pharmacologic correction of PAP-related abnormalities in murine macrophages in vitro and in vivo
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