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Phagocytosis of Hemozoin Enhances Matrix Metalloproteinase-9 Activity and TNF-α Production in Human Monocytes: Role of Matrix Metalloproteinases in the Pathogenesis of Falciparum Malaria1

Matrix metalloproteinase-9 (MMP-9), secreted by activated monocytes, degrades matrix proteins, disrupts basal lamina, and activates TNF-α from its precursors. In turn, TNF-α enhances synthesis of MMP-9 in monocytes. We show here that trophozoite-parasitized RBCs/hemozoin-fed adherent human monocytes displayed increased MMP-9 activity and protein/mRNA expression, produced TNF-α time-dependently, and showed higher matrix invasion ability. MMP-9 activation was specific for trophozoite/hemozoin-fed monocytes, was dependent on TNF-α production, and abrogated by anti-TNF-α Ab and by a specific inhibitor of MMP-9/MMP-13 activity. Hemozoin-induced enhancement of MMP-9 and TNF-α production would have a 2-fold effect: to start and feed a cyclic reinforcement loop in which hemozoin enhances production of TNF-α, which in turn induces both activation of MMP-9 and shedding of TNF-α into the extracellular compartment; and, second, to disrupt the basal lamina of endothelia. Excess production of TNF-α and disruption of the basal lamina with extravasation of blood cells into perivascular tissues are hallmarks of severe malaria. Pharmacological inhibition of MMP-9 may offer a new chance to control pathogenic mechanisms in malaria.