TNF-induced microvascular pathology: active role for platelets and importance of the LFA-1/ICAM-1 interaction.
Pathogenic mechanisms of brain microvascular injury were studied in an experimental model of cerebral malaria (CM). The lesion, leading to perivascular microhemorrhages, is due to cytokine overproduction, and is associated with the sequestration of macrophages and parasitized erythrocytes in cerebral venules. In this in vivo model, we demonstrate that platelets are critical effectors of the neurovascular injury. First, electron microscopy indicated that during CM platelets adhere to and probably damage brain endothelial cells. Second, radiolabelled platelet distribution studies indicated that platelets sequestered in the brain and lung vasculature during CM. Non-cerebral malaria was not associated with cerebral sequestration of platelets. Third, in vivo treatment with a mAb to LFA-1 (which is expressed on platelets) selectively abrogated the cerebral sequestration of platelets, and this correlated with prevention of CM. Fourth, malaria-infected animals rendered thrombocytopenic were significantly protected against CM, further indicating that platelets are central to the pathogenesis of CM. Thus, a CD11a-dependent interaction between platelets and endothelial cells appears pivotal to microvascular damage. These data suggest a novel mechanism of action for anti-LFA-1 mAb in vivo and illustrate an unexpected role of platelets, in addition to monocytes, in vascular pathology.
Grau
G E
GE
Department of Pathology, CMU, University of Geneva, Switzerland.
Tacchini-Cottier
F
F
Vesin
C
C
Milon
G
G
Lou
J N
JN
Piguet
P F
PF
Juillard
P
P
D000818:Animals; D001792:Blood Platelets / Q000502:physiology* / Q000648:ultrastructure; D001921:Brain / Q000098:blood supply* / Q000473:pathology; D002196:Capillaries / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D004195:Disease Models, Animal; D018799:Intercellular Adhesion Molecule-1; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D016779:Malaria, Cerebral / Q000473:pathology*; D051379:Mice; D008808:Mice, Inbred CBA; D008854:Microscopy, Electron; D010962:Plasmodium berghei; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D015815:Cell Adhesion Molecules; D016169:Lymphocyte Function-Associated Antigen-1; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1