ABSTRACT
Increasing attention is given to the finding that macrophages under hypoxia are capable of controlling infection by the intracellular protozoan parasite Leishmania amazonensis. The hypoxia-inducible factor (HIF)-1α has been shown to play an essential role in this enhanced innate immune response. Our study aimed to explore the HIF-1α-dependent mechanisms leading to reduced survival of the parasites residing in macrophages under low oxygen conditions. Hypoxia triggered (Pâ¯<â¯0.01) NADPH oxidase 2 (Nox2) expression and reactive oxygen species (ROS) production in J774 macrophages upon 24-h infection with L. amazonensis. Furthermore, increased (Pâ¯<â¯0.01) expression levels of HIF-1α and macrophage migration inhibitory factor (MIF) were detected in the infected cells grown at 3% oxygen tension. We found that either HIF-1α silencing, Nox2 inhibition or MIF antagonism caused a significant (Pâ¯<â¯0.05) reversal of the improved leishmanicidal activity displayed by the hypoxic phagocytes. Taken together, our current results suggest that, under conditions of limited availability of oxygen, activation of the HIF-1α/MIF axis via Nox2/ROS induction promotes killing of L. amazonensis amastigotes by macrophages. Such protective mechanism might operate in L. amazonensis-infected tissues where low oxygen levels prevail.
