Peroxisome proliferator-activated receptor-gamma is deficient in alveolar macrophages from patients with alveolar proteinosis.
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.
Bonfield
Tracey L
TL
Department of Pulmonary and Critical Care Medicine, 9500 Euclid Avenue, Cleveland Clinic Foundation, Desk A90, Cleveland, OH 44195-5038. thomasm@ccf.org
Farver
Carol F
CF
Barna
Barbara P
BP
Malur
Anagha
A
Abraham
Susamma
S
Raychaudhuri
Baisakhi
B
Kavuru
Mani S
MS
Thomassen
Mary Jane
MJ
D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D016676:Macrophages, Alveolar / Q000166:cytology / Q000378:metabolism*; D011649:Pulmonary Alveolar Proteinosis / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D018955:CD36 Antigens; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor