Open AccessTargeting cholesterol homeostasis in lung diseases
Author(s) -
Anthony Sallese,
Takuji Suzuki,
Cormac McCarthy,
James P. Bridges,
Alyssa Filuta,
Paritha Arumugam,
Kenjiro Shima,
Yan Ma,
Matthew Wessendarp,
Darcey Black,
Claudia Chalk,
Brenna Carey,
Bruce C. Trapnell
Publication year - 2017
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/s41598-017-10879-w
Subject(s) - cholesterol , alveolar macrophage , pulmonary surfactant , macrophage , pulmonary alveolar proteinosis , chemistry , in vivo , granulocyte macrophage colony stimulating factor , phospholipid , lung , pharmacology , immunology , medicine , endocrinology , in vitro , biology , cytokine , biochemistry , microbiology and biotechnology , membrane
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.