Pathogenic role of P-selectin in experimental cerebral malaria: importance of the endothelial compartment.
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.
Combes
Valéry
V
Experimental Parasitology Unit, Faculty of Medicine, Institut Fédératif de Recherche 48, Université de la Méditerranée, Marseille Cedex, France.
Rosenkranz
Alexander R
AR
Redard
Mireille
M
Pizzolato
Giampaolo
G
Lepidi
Hubert
H
Vestweber
Dietmar
D
Mayadas
Tanya N
TN
Grau
Georges E
GE
D000818:Animals; D001792:Blood Platelets / Q000502:physiology; D001921:Brain / Q000098:blood supply* / Q000473:pathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008168:Lung / Q000098:blood supply / Q000473:pathology; D016779:Malaria, Cerebral / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D019007:P-Selectin / Q000502:physiology*; D010962:Plasmodium berghei
D019007:P-Selectin