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(American Journal of Pathology. 2004;164:781-786.)
© 2004 American Society for Investigative Pathology

Short Communication

Pathogenic Role of P-Selectin in Experimental Cerebral Malaria

Importance of the Endothelial Compartment

Valéry Combes^*, Alexander R. Rosenkranz, Mireille Redard, Giampaolo Pizzolato, Hubert Lepidi, Dietmar Vestweber^¶, Tanya N. Mayadas and Georges E. Grau^*

From the Experimental Parasitology Unit,^* Faculty of Medicine, Institut Fédératif de Recherche 48, Université de la Méditerranée, Marseille Cedex, France; the Department of Pathology, Vascular Research Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; University of Geneva, Switzerland; Rickettsia Unit, Centre National de la Recherche Scientifique Unité Propre de Recherche et d’Enseignement Supérieur A 6020, Faculty of Medicine, Université de la Méditerranée, Marseille Cedex, France; and Institute of Cell Biology,^¶ University of Münster, Münster, Germany

P-selectin is a leukocyte adhesion receptor expressed on the surface of activated platelets and endothelial cells. Its role in the pathogenesis of cerebral malaria was explored in a murine model of cerebral malaria. Infection of mice with Plasmodium berghei ANKA led to P-selectin up-regulation in brain vessels of cerebral malaria-susceptible mice but not of cerebral malaria-resistant mice. Treatment of susceptible mice with anti-mouse P-selectin mAb failed to prevent the development of the neurological syndrome. However, P-selectin-deficient mice infected with Plasmodium berghei ANKA had a cumulative incidence of cerebral malaria which was significantly reduced compared to wild-type animals (4.5% versus 80%, respectively), despite identical levels of parasitemia, platelet and leukocyte accumulation. To determine whether P-selectin on platelets and/or endothelium was responsible for the microvascular pathology, cerebral malaria was assessed in chimeric mice deficient in platelet or endothelial P-selectin, which were generated by bone marrow transplantation. Mice deficient only in endothelial P-selectin did not show any sign of cerebral malaria (vascular plugging, hemorrhages, or edema), while mice lacking only platelet P-selectin showed signs of cerebral malaria similar to that seen in wild-type mice. These results indicate that endothelial P-selectin plays an important role in the pathogenesis of cerebral malaria.

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