Leishmania infantum-exploited Nrf2 transcription factor as a virulence process to escape macrophage-driven ferroptosis-like leishmanicidal process

Abstract

AbstractMacrophages are the main effector cells duringLeishmaniainfection. They contribute to the detection and elimination ofLeishmania spp.and may also promote parasite resilience. Here, we report that the activation of the transcription factor Nrf2 in macrophages plays a pivotal role in the progression ofLeishmania infantuminfection by controlling inflammation and redox balance of macrophages. We also highlight the involvement of NOX2/ROS axis in the early Nrf2 activation and subsequently of PGE2/EP2r signalling in the sustainment of Nrf2 activation uponL. infantuminfection. Moreover, we establish macrophage-driven ferroptosis-like process as a cell death program ofL. infantumand the protective effect of Nrf2 in macrophages againstL. infantumdeath. Altogether, these results identify Nrf2 as a critical factor for the susceptibility ofLeishmania infantuminfection, highlighting Nrf2 as a promising pharmacological target for the development of new therapeutic approaches for the treatment of visceral leishmaniasis.