title: MIF-driven activation of macrophages induces killing of intracellular Trypanosoma cruzi dependent on endogenous production of tumor necrosis factor, nitric oxide and reactive oxygen species.
abstract: The proinflammatory cytokine macrophage migration inhibitory factor (MIF) is a key player in innate immunity. MIF has been considered critical for controlling acute infection by the protozoan Trypanosoma cruzi, but the underlying mechanisms are poorly understood. Our study aimed to analyze whether MIF could favor microbicidal activity of the macrophage, a site where T. cruzi grows and the initial effector cell against this parasite. Using murine macrophages infected in vitro, we examined the effect of MIF on their parasiticidal ability and attempted to identify inflammatory agents involved in MIF-induced protection. Our findings show that MIF is readily secreted from peritoneal macrophages upon T. cruzi infection. MIF activates both primary and J774 phagocytes boosting the endogenous production of tumor necrosis factor-alpha via mitogen-activated protein kinase p38 signaling, as well as the release of nitric oxide and reactive oxygen species, leading to enhanced pathogen elimination. MIF can also potentiate the effect of interferon-gamma on T. cruzi killing by J774 and mouse peritoneal macrophages, rendering these cells more competent in reducing intracellular parasite burden. The present results unveil a novel innate immune pathway that contributes to host defense and broaden our understanding of the regulation of inflammatory mediators implicated in early parasite containment that is decisive for resistance to T. cruzi infection.
authors: Servicio de Parasitología-Chagas, Hospital de Niños "Dr. Ricardo Gutiérrez", Ciudad de Buenos Aires, Argentina. Electronic address: romicutru@yahoo.com.ar.
authors: Romina A
authors: RA
authors: Cutrullis
authors: Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPaM-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina. Electronic address: ppetray@yahoo.com.
authors: Patricia B
authors: PB
authors: Petray
authors: Servicio de Parasitología-Chagas, Hospital de Niños "Dr. Ricardo Gutiérrez", Ciudad de Buenos Aires, Argentina. Electronic address: ricardocorral56@hotmail.com.
authors: Ricardo S
authors: RS
authors: Corral
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D005260:Female; D006790:Host-Parasite Interactions / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology*; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology* / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D010587:Phagocytosis / Q000276:immunology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014349:Trypanosoma cruzi / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000378:metabolism*
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D017382:Reactive Oxygen Species; D048069:Tumor Necrosis Factors; D009569:Nitric Oxide
keywords: Macrophage activation; Macrophage migration inhibitory factor; Nitric oxide; Parasiticidal activity; Reactive oxygen species; Trypanosoma cruzi infection; Tumor necrosis factor