Sensing environmental lipids by dendritic cell modulates its function.
Because of its oxidative modification during the acute-phase response to an aggression, low density lipoprotein (LDL) can be regarded as a source of lipid mediators that can act both to promote and inhibit inflammation. This can be exemplified by the production of anti-inflammatory oxidized fatty acids and proinflammatory lysophosphatidylcholine (LPC) during LDL oxidation. We have shown previously that oxidized LDL (oxLDL) plays an active role at the interface between innate and adaptive immunity by delivering instructive molecules such as LPC, which promotes mature dendritic cell (DC) generation from differentiating monocytes. It is shown in this study that LPC affects the signaling pathway of peroxisome proliferator-activated receptors (PPARs). LPC-induced DC maturation is associated with complete inhibition of PPARgamma activity and up-regulation of the activity of an uncharacterized nuclear receptor that bind peroxisome proliferator response element. Oxidized fatty acids generated during LDL oxidation are natural ligands for PPARgamma and inhibit oxLDL- and LPC-induced maturation. Inhibition experiments with synthetic PPARgamma ligands suggested a PPARgamma-dependent and independent effect of LPC on DC maturation. Therefore, the relative amount of oxidized fatty acids and LPC influences the immunological functions of oxLDL on DC, in part by regulating the PPAR pathway. By sensing the biochemical composition of lipoprotein particles, the innate immune system may thus identify various endogenous signals that influence the immune response during the acute-phase reaction. The therapeutic emulsion intralipid also blocks LPC action on PPAR activity and DC maturation. Intralipid may thus be an alternative therapeutic strategy for some chronic inflammatory diseases.
Coutant
Frédéric
F
Institut Fédératif de Recherche 128, BioSciences Lyon-Gerland, Institut National de la Santé et de la Recherche Médicale, Unité 503, 21 Avenue Tony Garnier, 69007 Lyon, France.
Agaugué
Sophie
S
Perrin-Cocon
Laure
L
André
Patrice
P
Lotteau
Vincent
V
D000209:Acute-Phase Proteins / Q000378:metabolism* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D005217:Fat Emulsions, Intravenous / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D008024:Ligands; D008041:Linoleic Acids / Q000494:pharmacology; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D008244:Lysophosphatidylcholines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010084:Oxidation-Reduction; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism
D000209:Acute-Phase Proteins; D004268:DNA-Binding Proteins; D005217:Fat Emulsions, Intravenous; D006131:Growth Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D008024:Ligands; D008041:Linoleic Acids; D044243:Linoleic Acids, Conjugated; D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; C099252:oxidized low density lipoprotein; C024347:9-hydroxy-10,12-octadecadienoic acid; C024348:13-hydroxy-9,11-octadecadienoic acid; C027356:11-hydroxy-5,8,12,14-eicosatetraenoic acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D007371:Interferon-gamma; C039671:ciglitazone