Leishmania infantum exploits the anti-ferroptosis effects of Nrf2 to escape cell death in macrophages.

Macrophages are major host cells for the protozoan Leishmania parasite. Depending on their activation state, they either contribute to the detection and elimination of Leishmania spp. or promote parasite resilience. Here, we report that the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in macrophages plays a pivotal role in the progression of Leishmania infantum infection by controlling inflammation and redox balance of macrophages. We also highlight the involvement of the NOX2/reactive oxygen species (ROS) axis in early Nrf2 activation and, subsequently, prostaglandin E2 (PGE2)/EP2r signaling in the sustenance of Nrf2 activation upon infection. Moreover, we establish a ferroptosis-like process within macrophages as a cell death program of L. infantum and the protective effect of Nrf2 in macrophages against L. infantum death. Altogether, these results identify Nrf2 as a critical factor for the susceptibility of L. infantum infection, highlighting Nrf2 as a promising pharmacological target for the development of therapeutic approaches for the treatment of visceral leishmaniasis. [Display omitted] • ROS and the PGE2/EP2 axis mediate Nrf2 activation in MΦs to promote L.i. growth • Nrf2 promotes L.i. infection via an anti-oxidant and anti-inflammatory profile of MΦs • Nrf2 in MΦs protects L.i. from lipid peroxidation, preventing its death by ferroptosis Blot et al. demonstrate that Nrf2 is a critical transcription factor that protects Leishmania infantum from lipid peroxidation and death by a ferroptosis-like process through the induction of an anti-oxidant and anti-inflammatory profile of macrophages. Hence, pharmacological inhibition of Nrf2 constitutes a promising target for the treatment of visceral leishmaniasis. [ABSTRACT FROM AUTHOR]