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.

Macrophage heterogeneity and cholesterol homeostasis: Classically-activated macrophages are associated with reduced cholesterol accumulation following treatment with oxidized LDL

“…Our results show that TNFα is also capable of causing a decrease in both CD36 and MSR1 which has been confirmed by several in vitro studies in different models [53][54][55][56]. MSR1 expression appears to be regulated both transcriptionally and post-transcriptionally and likely involves the phosphatidylinositol 3-kinase/Rac1/PAK/JNK and phosphatidylinositol 3-kinase/Rac1/PAK/p38 pathways [53,54].…”

Lipid storage by adipose tissue macrophages regulates systemic glucose tolerance

“…However, LPL silencing decreased the expression of CD36 and DGAT2, while the expression of other PPAR target genes remained unchanged. Although additional work would be needed to unravel the mechanism whereby LPL silencing secondarily decreases CD36 and DGAT2 gene expression, previous studies (8,22) as well as our work suggest that different transcription factors, coactivators, or repressors may be involved in the transcriptional regulation of lipogenic genes in macrophages deficient in LPL.…”

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

“…When macrophages are cultured from human monocytes treated with heme, they are resistant to lipid accumulation because the expression of the oxLDL SRs, including CD36, is significantly suppressed (53). However, oxLDL-mediated activation of Nrf2 in monocyte-derived macrophages appears to play a promiscuous role by activating expression of both HO-1 and CD36 (21,126). The latter is the principal SR in foam cell formation (71).…”