Targeting cholesterol homeostasis in lung diseases

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.

Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

“…This functional response is characterized by the cells being predominantly cholesterol-laden. In pulmonary alveolar proteinosis, increased cholesterol/lipid accumulation within AMs might be mediated by defective GM-CSF signaling and, as a consequence, reduced PPARG and cholesterol transporter (ABCG1) expression (De Aguiar Vallim et al, 2017;Sallese et al, 2017;Trapnell et al, 2019). This mechanism is unlikely in COPD since we do not observe clear downregulation of either PPARG ( Figure S3F) or ABCG1 ( Figure 3D).…”

“…Thus, they are highly associated with lipid metabolism. Failure of this 'accessory' function is reflected by pulmonary alveolar proteinosis (PAP), in which defective GM-CSF signaling in AMs causes an accumulation of surfactant-derived lipids in AMs and the AS (De Aguiar Vallim et al, 2017;Sallese et al, 2017;Trapnell et al, 2019). However, due to the expression of ABCG1 in AMs from COPD patients, the accumulation of cholesteryl ester must be due to alternative molecular mechanisms than in PAP (De Aguiar Vallim et al, 2017;Baker et al, 2010).…”

GM-CSF in inflammation

“…Consistent with these other roles, GM-CSF gene-deficient mice showed minimal changes in steady state myelopoiesis but developed pulmonary alveolar proteinosis (PAP) as the major phenotype indicating GM-CSF involvement in lung surfactant homeostasis (Dranoff et al, 1994;Stanley et al, 1994); this finding indicated a role for GM-CSF in alveolar macrophage development, which has been found to be dependent on the transcription factor PPARγ (Schneider et al, 2014). It has been proposed recently that GM-CSF is required for cholesterol clearance in alveolar macrophages, with a reduction in this clearance being the primary macrophage defect driving PAP (Sallese et al, 2017;Trapnell et al, 2019). This lung data suggest a fundamental role for GM-CSF in lipid (cholesterol) metabolism consistent with a proposed protective role in atherosclerosis (Ditiatkovski et al, 2006;see below).…”

Pulmonary Alveolar Proteinosis Syndrome

“…Decreased cholesterol clearance leads to the foamy appearance of macrophages and is conceivably the rate limiting step of macrophage dysfunction in PAP. 106,107 Reduced GM-CSF signaling (either due to autoantibodies or receptor dysfunction) results in reduced (peroxisome proliferator-activated receptor gamma) PPARγ gene expression in macrophages of primary PAP. In turn this results in lower expression of the cell surface cholesterol transporters ABCG1 and ABCA1.…”