Lesion associated expression of urokinase-type plasminogen activator receptor (uPAR, CD87) in human cerebral malaria

Blood-brain barrier disintegration and inflammatory cell recruitment are key processes in the pathogenesis of cerebral malaria (CM). Recent data provide convincing evidence that the serine protease urokinase-type plasminogen activator receptor (uPAR) is a key molecule in promoting cell adhesion and spreading. We have now analyzed expression of urokinase-type plasminogen activator receptor (uPAR, CD87), which is part of a cell surface associated proteolytic system, in brains of eight CM patients and seven neuropathologically unaltered and diseased controls by immunohistochemistry. Double labeling experiments with antibodies directed against CD68 (macrophages/microglial cells), myeloid-related protein (MRP8), and glial fibrillary acid protein (GFAP) confirmed the nature of uPAR expressing cells. We observed focal accumulation of uPAR expressing macrophages/microglial cells in Dürck's granulomas and adjacent to petechial hemorrhages, in astrocytes, and in endothelial cells. In contrast, focal uPAR expression in macrophages/microglial cells but not in astrocytes was found in microglial nodules of toxoplasmic encephalitis and in the cellular infiltrate of bacterial meningitis. Normal brains showed only faint uPAR expression in endothelial cells. We conclude from these data that lesion-associated uPAR expression at least in part contributes to blood-brain barrier alteration and immunologic dysfunction in CM patients.