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TNF-induced microvascular pathology: active role for platelets and importance of the LFA-1/ICAM-1 interaction
G E Grau1, F Tacchini-Cottier, C Vesin
1Department of Pathology, CMU, University of Geneva, Switzerland.
Abstract:
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.
Insights
Platelets critically damage brain blood vessels during cerebral malaria (CM). Blocking platelet interaction with endothelial cells via anti-LFA-1 antibodies prevents CM, highlighting platelets
Area of Science:
- Neuroscience
- Immunology
- Vascular Biology
Background:
- Cerebral malaria (CM) involves brain microvascular injury, cytokine overproduction, and sequestration of infected cells.
- Pathogenic mechanisms of neurovascular damage in CM require further elucidation.
Purpose of the Study:
- To investigate the role of platelets in the pathogenesis of brain microvascular injury during experimental cerebral malaria.
- To explore the potential of targeting platelet-endothelial interactions for CM prevention.
Main Methods:
- Utilized an in vivo experimental model of cerebral malaria.
- Employed electron microscopy to examine platelet-endothelial interactions.
- Conducted radiolabeled platelet distribution studies.
- Administered anti-LFA-1 monoclonal antibody (mAb) and induced thrombocytopenia in infected animals.
Main Results:
- Platelets adhere to and damage brain endothelial cells during CM.
- Platelets sequestered in cerebral and lung vasculature during CM, but not in non-cerebral malaria.
- Anti-LFA-1 mAb treatment prevented cerebral platelet sequestration and CM.
- Thrombocytopenic malaria-infected animals were protected against CM.
Conclusions:
- Platelets are critical effectors of neurovascular injury in cerebral malaria.
- A CD11a-dependent interaction between platelets and endothelial cells is pivotal to microvascular damage.
- Targeting LFA-1 offers a novel therapeutic strategy for preventing CM.