Severe
malaria, including
cerebral malaria (CM), is characterized by the sequestration of parasitized erythrocytes in the microvessels after cytoadherence to endothelial cells. Products of parasite origin, such as
haemozoin (HZ), contribute to the pathogenesis of severe
malaria by interfering with host inflammatory response. In human monocytes, HZ enhanced the levels of
matrix metalloproteinase-9 (MMP-9), a
protease involved in
neuroinflammation. Here the effects of HZ on the regulation of
MMPs by the human microvascular endothelial cell line HMEC-1 were investigated. Cells treated with natural (n)HZ appeared elongated instead of polygonal, and formed microtubule-like vessels on synthetic basement membrane. nHZ enhanced total gelatinolytic activity by inducing
proMMP-9 and MMP-9 without affecting basal MMP-2. The level of the endogenous tissue inhibitor of MMP-9 (TIMP-1) was not altered by nHZ, while
TIMP-2, the MMP-2 inhibitor, was enhanced. Additionally, nHZ induced MMP-1 and MMP-3, two
enzymes sequentially involved in collagenolysis and
proMMP-9 proteolytic activation.
Lipid-free HZ did not reproduce nHZ effects. Present data suggest that the
lipid moiety of HZ alters the
MMP/TIMP balances and promotes the proteolytic activation of
proMMP-9 in HMEC-1, thereby enhancing total gelatinolytic activity, cell activation and
inflammation. These findings might help understanding the mechanisms of blood brain barrier damage during CM.