PPARgamma-dependent regulation of human macrophages in phagocytosis of apoptotic cells.
Macrophages acquire their capacity for efficient phagocytosis of apoptotic cells during their differentiation from monocytes. The peroxisome proliferator-activated receptor gamma (PPARgamma) is highly up-regulated during this maturation program. We report that addition of PPARgamma antagonist during differentiation of human monocytes to macrophages significantly reduced the capacity of macrophages to engulf apoptotic neutrophils, but did not influence phagocytosis of opsonized bacteria. Macrophage-specific deletion of PPARgamma in mice also resulted in decreased uptake of apoptotic cells. The antagonist acted in a dose-dependent manner during the differentiation of human macrophages and could also reverse the previously observed augmentation of phagocytosis by glucocorticoids. Blocking activation of PPARgamma led to down-regulation of molecular elements (CD36, AXL, TG2 and PTX3) of the engulfment process. Inhibition of PPARgamma-dependent gene expression did not block the anti-inflammatory effect of apoptotic neutrophils or synthetic glucocorticoid, but significantly decreased production of IL-10 induced by LPS. Our results suggest that during differentiation of macrophages natural ligands of PPARgamma are formed, regulating the expression of genes responsible for effective clearance of apoptotic cells and macrophage-mediated inflammatory responses.
Majai
Gyöngyike
G
Department of Biochemistry and Molecular Biology, Signalling and Apoptosis Research Group of the Hungarian Academy of Sciences, Research Centre for Molecular Medicine, University of Debrecen, Medical and Health Science Centre, Debrecen, Hungary.
Sarang
Zsolt
Z
Csomós
Krisztián
K
Zahuczky
Gábor
G
Fésüs
László
L
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000276:immunology / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D047495:PPAR gamma; D012333:RNA, Messenger