Platelet-activating factor receptor is essential for the development of experimental cerebral malaria

Norinne Lacerda-Queiroz, David H. Rodrigues, Márcia C. Vilela, Milene A. Rachid, Frederico M. Soriani, Lirlndia P. Sousa, Roberta D.L. Campos, Valerie F.J. Quesniaux, Mauro M. Teixeira, Antonio L. Teixeira

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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 bloodbrain 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.

Original languageEnglish (US)
Pages (from-to)246-255
Number of pages10
JournalAmerican Journal of Pathology
Volume180
Issue number1
DOIs
StatePublished - Jan 2012
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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