Nrf2, a PPARγ Alternative Pathway to Promote CD36 Expression on Inflammatory Macrophages: Implication for Malaria

PLoS Pathogens

Lise Lefèvre¹  Agnès Aubouy¹  Antoine Berry¹  Rose-Anne Lavergne¹  Bernhard Ryffel¹  Etienne Meunier²  Christophe Dardenne²  Bernard Pipy²  David Olagnier²  Agnès Coste²  Françoise Benoit-Vical² 

[1] Université de Toulouse, UPS, UMR 152 IRD, Pharma-Dev, Toulouse, France;Université de Toulouse, UPS, UMR-MD3, Relations Hôte-Parasites Polarisation des Macrophages et Récepteurs Nucléaires dans les Pathologies Inflammatoires et Infectieuses, Toulouse, France

关键词: Macrophages;    Inflammation;    Malaria;    Phagocytosis;    Parasitic diseases;    Malarial parasites;    Plasmodium;    Transcription factors;   

DOI  :  10.1371/journal.ppat.1002254

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY