Peroxisome Proliferator-Activated Receptor-γ Is Deficient in Alveolar Macrophages from Patients with Alveolar Proteinosis

Abstract

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-activated, nuclear transcription factor that regulates genes involved in lipid and glucose metabolism, inflammation, and other pathways. The hematopoietic growth factor, granulocyte macrophage colony-stimulating factor (GM-CSF), is essential for lung homeostasis and is thought to regulate surfactant clearance, but mechanisms involved are unknown. GM-CSF is reported to stimulate PPAR-gamma, but the activation status of PPAR-gamma in human alveolar macrophages has not been defined. In pulmonary alveolar proteinosis (PAP), a rare interstitial lung disease, surfactant accumulates in alveolar airspaces, resident macrophages become engorged with lipoproteinaceous material, and GM-CSF deficiency is strongly implicated in pathogenesis. Here we show that PPAR-gamma mRNA and protein are highly expressed in alveolar macrophages of healthy control subjects but severely deficient in PAP in a cell-specific manner. Further, we show that the PPAR-gamma-regulated lipid scavenger receptor, CD36, is also deficient in PAP. PPAR-gamma and CD36 deficiency are not intrinsic to PAP alveolar macrophages, but can be upregulated by GM-CSF therapy. Moreover, GM-CSF treatment of patients with PAP fully restores PPAR-gamma to healthy control levels. Based upon these novel findings, we hypothesize that GM-CSF regulates lung homeostasis via PPAR-gamma-dependent pathways.

New mutations in the SLC7A7 gene of two chinese sisters with lysinuric protein intolerance

“…According to Amelia Barilli study CD204 (Scavenger Receptor A, SR‐A), a protein involved in cholesterol uptake;5 PPAR (Peroxisome Proliferator‐Activated Receptor‐g), a key mediator of surfactant catabolism by alveolar macrophages (AM),6, 7 and PU.1, a transcription factor that promotes AM maturation, differentiation, and surfactant catabolism 8. The treatment with rGM‐CSF induced marked expression of all these markers, functioning alveolar macrophages 9…”

Peroxisome Proliferator‐Activated Receptors: Potential Therapeutic Targets in Lung Disease?

“…101 The results of defective surfactant clearance include accumulation of surfactant in alveolar air spaces and engorgement of alveolar macrophages with proteinaceous material. A contributing factor in this disease is decreased expression of granulocyte macrophage colonystimulating factor (GM-CSF).…”

“…As in pulmonary sarcoidosis, PAP patients have reduced levels of PPARg in alveolar macrophages. 100,101 This likely results from the loss of GM-CSF, as GM-CSF therapy restores PPARg levels to those of healthy controls. Interestingly, PPARg levels in epithelial cells from PAP patients are normal, providing further evidence for cell-specific mechanisms for regulating PPARg expression and a cell type-specific etiology for this disease.…”

Paediatric interstitial lung disease

“…Subsequently, auto-antibodies against GM-CSF were found in late-onset PAP [41,42]. It would appear that GM-CSF regulates surfactant homeostasis via CD36 peroxisome proliferatoractivated receptor (PPAR)-␥ [45]. GM-CSF therapy in PAP restores PPAR-␥ levels to normal.…”