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.
Highlights
Mononuclear phagocytes represent the first line of innate immune defense against pathogens through mechanisms involving recognition by pattern-recognition receptors (PRRs) of highly structurally conserved microbial structures, known as pathogenassociated molecular patterns [1]
To assess whether TLR signaling directly leads to reduced CD36 expression or if the effects mediated by PGN or P.f. cs are dependent on TNF-a production, we evaluated CD36 protein level in presence of an anti-TLR2 antibody or etanercept, a potent TNF-a inhibitor
We demonstrated that inflammatory processes induced by TNF-a or TLR2 ligands downregulate CD36 expression on Swiss murine and human macrophages
Summary
Mononuclear phagocytes represent the first line of innate immune defense against pathogens through mechanisms involving recognition by pattern-recognition receptors (PRRs) of highly structurally conserved microbial structures, known as pathogenassociated molecular patterns [1]. Among the PRRs family, the class B scavenger receptor CD36, initially known as a receptor for the uptake of oxidatively low density lipoprotein, mediates the recognition and the elimination of apoptotic cells and bacteria [2,3]. The CD36 receptor recognizes Plasmodium falciparum parasitized-erythrocytes (PfPEs), resulting in a CD36dependent nonopsonic phagocytosis of PfPEs and a decrease in parasite-induced TNF-a secretion [4]. CD36-deficient macrophages displayed a marked phagocytic defect for parasitized erythrocytes compared with wild-type macrophages [5]. CD362/2 mice present a defect in parasite clearance [5]
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