title: Role of the tumor necrosis factor receptor 2 (TNFR2) in cerebral malaria in mice.
abstract: Infection of susceptible mice with Plasmodium berghei Anka leads to a syndrome of severe or cerebral malaria. Tumor necrosis factor (TNF) contributes to this syndrome, apparently by acting on its receptor 2 (TNFR2) because TNFR1-/- are susceptible, whereas TNFR2-/- mice are resistant. In this work, we confirmed the essential role of the TNFR2 in cerebral malaria because 6 to 8 days after Plasmodium berghei Anka infection, hypothermia, coma, and death were observed in +/+ or TNFR1-/-, but never in TNFR2-/-, mice. TNF production, evaluated by the serum levels or the mRNA levels in the brain, spleen or lung, was similar in +/+, TNFR1-/-, or TNFR2-/- mice. Macrophage or parasitized red blood cell sequestration in brain or lung was similar in TNFR1-/- and TNFR2-/- mice. Accordingly, up-regulation of CD54 or CD40 in brain or lung was also similar in TNFR1-/- or TNFR2-/- mice. Platelet loss, manifested by thrombocytopenia and the presence of microparticles in plasma, was similar in TNFR1-/- or TNFR2-/- mice. Breakdown of the blood-brain barrier, detected by the diffusion of tracers, was attenuated in both TNFR1-/- and TNFR2-/-, compared with +/+, mice. Endothelial cells from brain capillaries, examined by transmission electron microscopy, were similar in infected TNFR1-/- or TNFR2-/- mice, whereas the basement membrane was enlarged in TNFR1-/- mice. Hypothermic mice were also hyperglycemic, and this was evident in +/+ and TNFR1-/-, but not in TNFR2-/-, mice. In addition, infected +/+ and TNFR1-/- mice became insulin resistant, while in contrast TNFR2-/- became extremely insulin sensitive. This study supports the possibility that coma and death are mediated not by cell sequestration or breakdown of vascular permeability, similar in TNFR1-/- or TNFR2-/- mice, but by metabolic disturbances selectively mediated by the TNFR2.
authors.affiliation: Department of Pathology, Universite de Geneve, Geneva, Switzerland. perre.piguet@medecine.unige.ch
authors.forename: Pierre François
authors.initials: PF
authors.lastname: Piguet
authors.forename: Chen Da
authors.initials: CD
authors.lastname: Kan
authors.forename: Christian
authors.initials: C
authors.lastname: Vesin
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D001921:Brain / Q000098:blood supply; D015704:CD4 Antigens / Q000235:genetics; D019013:CD40 Antigens / Q000235:genetics; D023201:CD40 Ligand / Q000235:genetics; D002199:Capillary Permeability; D003128:Coma / Q000209:etiology; D004912:Erythrocytes / Q000502:physiology; D007328:Insulin / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology; D016779:Malaria, Cerebral / Q000209:etiology* / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D012333:RNA, Messenger / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D013921:Thrombocytopenia / Q000209:etiology
chemical_list: D015703:Antigens, CD; D015704:CD4 Antigens; D019013:CD40 Antigens; D007328:Insulin; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D023201:CD40 Ligand