title: Heme dampens T-cell sequestration by modulating glial cell responses during rodent cerebral malaria.
abstract: Cerebral malaria is the deadliest complication of Plasmodium falciparum infection. Its pathophysiology is associated with a strong pro-inflammatory reaction and the activation of glial cells. Among modulators released during the infection, heme seems to play a controversial role in the pathophysiology of malaria. Herein, we first investigated the phenotype of glial cells during cerebral malaria in C57BL/6 mice infected with P. berghei ANKA. Given the fact that high levels of heme were associated with cerebral malaria, we then investigated its impact on microglial, astrocyte, and T cell responses to further clarify its contribution in the neuropathophysiology. Surprisingly, we found that administration of heme twice a day from day three of infection induced the expression of the Heme oxygenase-1 (Hmox1) gene and prevented brain damages. More specifically, heme inhibited the M1 phenotype of microglia, hampered the activation of astrocytes, and decreased the cerebral expression of Ifng, Tnfa and Ip10. Heme might that way alter the migration of pathogenic CD4 and CD8 T lymphocytes within the brain observed during cerebral malaria. Taking into account that cerebral malaria results from a complex interplay between host- and parasite-derived factors, it is possible that genetic polymorphisms of Hmox1, which could be associated with the control of systemic levels of heme during P. falciparum infection, might explain its dual role and its contribution to the resistance to cerebral malaria.
authors.affiliation: Center for Infection and Immunity of Lille, CNRS UMR 8204, Université de Lille, Institut Pasteur de Lille, Lille, France; Département des Sciences Biologiques, Université du Québec à Montréal, Montréal, Canada.
authors.forename: Esther
authors.initials: E
authors.lastname: Dalko
authors.affiliation: Center for Infection and Immunity of Lille, CNRS UMR 8204, Université de Lille, Institut Pasteur de Lille, Lille, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Genete
authors.affiliation: Imaging Platform, Research Pole, Lille University Hospital, Lille, France; Université de Lille, UDSL, EA 1046 Lille, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Auger
authors.affiliation: Center for Infection and Immunity of Lille, CNRS UMR 8204, Université de Lille, Institut Pasteur de Lille, Lille, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Dovergne
authors.affiliation: Center for Infection and Immunity of Lille, CNRS UMR 8204, Université de Lille, Institut Pasteur de Lille, Lille, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Lambert
authors.affiliation: Center for Infection and Immunity of Lille, CNRS UMR 8204, Université de Lille, Institut Pasteur de Lille, Lille, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Herbert
authors.affiliation: Center for Infection and Immunity of Lille, CNRS UMR 8204, Université de Lille, Institut Pasteur de Lille, Lille, France.
authors.forename: Pierre-André
authors.initials: PA
authors.lastname: Cazenave
authors.affiliation: Center for Infection and Immunity of Lille, CNRS UMR 8204, Université de Lille, Institut Pasteur de Lille, Lille, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Roland
authors.affiliation: Center for Infection and Immunity of Lille, CNRS UMR 8204, Université de Lille, Institut Pasteur de Lille, Lille, France. Electronic address: sylviane.pied@pasteur-lille.fr.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Pied
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology*; D001921:Brain / Q000276:immunology* / Q000469:parasitology*; D005260:Female; D006418:Heme / Q000008:administration & dosage / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D000069544:Infectious Encephalitis / Q000150:complications; D016779:Malaria, Cerebral / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology*; D010962:Plasmodium berghei / Q000472:pathogenicity; D013154:Spleen; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D006418:Heme; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: Astrocyte; Cerebral malaria; Heme; Hmox1; Inflammation; Microglia