RESTORE UMR 1301-INSERM 5070 CNRS EFS UPS, Toulouse, France.
Institute of Pharmacology and Structural Biology (IPBS), UMR5089 CNRS UPS, Toulouse, France.
Cell Rep. 2024 Sep 24;43(9):114720. doi: 10.1016/j.celrep.2024.114720. Epub 2024 Sep 7.
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.
巨噬细胞是原生动物利什曼原虫寄生虫的主要宿主细胞。根据其激活状态，它们要么有助于检测和消除利什曼原虫属，要么促进寄生虫的恢复力。在这里，我们报告说，转录因子红细胞生成 2 相关因子 2（Nrf2）在巨噬细胞中的激活在利什曼原虫感染的进展中起着关键作用，通过控制巨噬细胞的炎症和氧化还原平衡。我们还强调了 NOX2/活性氧（ROS）轴在早期 Nrf2 激活中的参与，以及随后在感染时前列腺素 E2（PGE2）/EP2r 信号在维持 Nrf2 激活中的作用。此外，我们在巨噬细胞中建立了类似于铁死亡的过程，作为利什曼原虫的细胞死亡程序，以及 Nrf2 在巨噬细胞中对利什曼原虫死亡的保护作用。总的来说，这些结果表明 Nrf2 是利什曼原虫感染易感性的关键因素，强调 Nrf2 是开发治疗内脏利什曼病的治疗方法的有前途的药理学靶点。
