title: Nrf2, a PPARγ alternative pathway to promote CD36 expression on inflammatory macrophages: implication for malaria.
abstract: CD36 is the major receptor mediating nonopsonic phagocytosis of Plasmodium falciparum-parasitized erythrocytes by macrophages. Its expression on macrophages is mainly controlled by the nuclear receptor PPARγ. Here, we demonstrate that inflammatory processes negatively regulate CD36 expression on human and murine macrophages, and hence decrease Plasmodium clearance directly favoring the worsening of malaria infection. This CD36 downregulation in inflammatory conditions is associated with a failure in the expression and activation of PPARγ. Interestingly, using siRNA mediating knock down of Nrf2 in macrophages or Nrf2- and PPARγ-deficient macrophages, we establish that in inflammatory conditions, the Nrf2 transcription factor controls CD36 expression independently of PPARγ. In these conditions, Nrf2 activators, but not PPARγ ligands, enhance CD36 expression and CD36-mediated Plasmodium phagocytosis. These results were confirmed in human macrophages and in vivo where only Nrf2 activators improve the outcome of severe malaria. Collectively, this report highlights that the Nrf2 transcription factor could be an alternative target to PPARγ in the control of severe malaria through parasite clearance.
authors.affiliation: Université de Toulouse, UPS, UMR-MD3, Relations Hôte-Parasites Polarisation des Macrophages et Récepteurs Nucléaires dans les Pathologies Inflammatoires et Infectieuses, Toulouse, France.
authors.forename: David
authors.initials: D
authors.lastname: Olagnier
authors.forename: Rose-Anne
authors.initials: RA
authors.lastname: Lavergne
authors.forename: Etienne
authors.initials: E
authors.lastname: Meunier
authors.forename: Lise
authors.initials: L
authors.lastname: Lefèvre
authors.forename: Christophe
authors.initials: C
authors.lastname: Dardenne
authors.forename: Agnès
authors.initials: A
authors.lastname: Aubouy
authors.forename: Françoise
authors.initials: F
authors.lastname: Benoit-Vical
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Agnès
authors.initials: A
authors.lastname: Coste
authors.forename: Antoine
authors.initials: A
authors.lastname: Berry
authors.forename: Bernard
authors.initials: B
authors.lastname: Pipy
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000096:biosynthesis*; D015536:Down-Regulation; D004912:Erythrocytes / Q000469:parasitology; D005260:Female; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D016778:Malaria, Falciparum / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D010587:Phagocytosis; D010963:Plasmodium falciparum / Q000276:immunology* / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D047495:PPAR gamma