Nrf2, a PPARγ alternative pathway to promote CD36 expression on inflammatory macrophages: implication for malaria

Area of Science:

• Immunology
• Infectious Diseases
• Molecular Biology

Background:

• CD36 is a key macrophage receptor for clearing Plasmodium falciparum-infected red blood cells.
• PPARγ typically regulates CD36 expression on macrophages.
• Inflammatory conditions impair CD36 expression and malaria parasite clearance.

Purpose of the Study:

• To investigate the mechanisms regulating CD36 expression during inflammation.
• To identify alternative therapeutic targets for severe malaria.

Main Methods:

• Utilized human and murine macrophages.
• Employed siRNA for Nrf2 knockdown.
• Generated Nrf2- and PPARγ-deficient macrophages.
• Administered Nrf2 activators and PPARγ ligands in vivo and in vitro.

Main Results:

• Inflammatory processes downregulate CD36 expression on macrophages, impairing Plasmodium clearance.
• This downregulation is linked to reduced PPARγ expression and activation.
• Nrf2 transcription factor controls CD36 expression independently of PPARγ during inflammation.
• Nrf2 activators, but not PPARγ ligands, enhance CD36 expression and Plasmodium phagocytosis.
• Nrf2 activators improved outcomes in a severe malaria model.

Conclusions:

• Nrf2 is a critical regulator of CD36 expression during inflammatory responses in malaria.
• Targeting Nrf2 offers a potential therapeutic strategy for severe malaria, independent of PPARγ pathways.