title: Platelet-activating factor receptor is essential for the development of experimental cerebral malaria.
abstract: Cerebral malaria is a severe form of the disease that may result, in part, from an overt inflammatory response during infection by Plasmodium falciparum. The understanding of the pathogenesis of cerebral malaria may aid in the development of better therapeutic strategies for patients. The immune response in cerebral malaria involves elevation of circulating levels of cytokines and chemokines associated with leukocyte accumulation and breakdown of the blood-brain barrier in the central nervous system. Platelet-activating factor (PAF) is a mediator of inflammation shown to orchestrate inflammatory processes, including recruitment of leukocytes and increase of vascular permeability. Using mice lacking the PAF receptor (PAFR(-/-)), we investigated the relevance of this molecule for the outcome and the neuroinflammatory process triggered by P. berghei ANKA, an experimental model of cerebral malaria. In PAFR(-/-) mice, lethality was markedly delayed and brain inflammation was significantly reduced, as demonstrated by histology, accumulation, and activation of CD8(+) T cells, changes in vascular permeability and activation of caspase-3 on endothelial cells and leukocytes. Similarly, treatment with the PAFR antagonist UK-74,505 delayed lethality. Taken together, the results suggest that PAFR signaling is crucial for the development of experimental cerebral malaria. Mechanistically, PAFR activation is crucial for the cascade of events leading to changes in vascular permeability, accumulation, and activation of CD8(+) T cells and apoptosis of leukocytes and endothelial cells.
authors.affiliation: Department of Cell Biology, Institute of Biological Sciences, Faculty of Medicine, Federal University of Minas Gerais, Minas Gerais, Brazil. norinneq@yahoo.com.br
authors.forename: Norinne
authors.initials: N
authors.lastname: Lacerda-Queiroz
authors.forename: David H
authors.initials: DH
authors.lastname: Rodrigues
authors.forename: Márcia C
authors.initials: MC
authors.lastname: Vilela
authors.forename: Milene A
authors.initials: MA
authors.lastname: Rachid
authors.forename: Frederico M
authors.initials: FM
authors.lastname: Soriani
authors.forename: Lirlândia P
authors.initials: LP
authors.lastname: Sousa
authors.forename: Roberta D L
authors.initials: RD
authors.lastname: Campos
authors.forename: Valerie F J
authors.initials: VF
authors.lastname: Quesniaux
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Teixeira
mesh_terms: D000818:Animals; D001923:Brain Chemistry; D053148:Caspase 3 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007962:Leukocytes / Q000502:physiology; D008213:Lymphocyte Activation; D016779:Malaria, Cerebral / Q000209:etiology* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*
chemical_list: D018925:Chemokines; D016207:Cytokines; D004095:Dihydropyridines; D007093:Imidazoles; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C073027:modipafant; D053148:Caspase 3