Figure 4

Principal mechanisms underlying Hz-dependent dysregulation of matrix metalloproteinase-9 (MMP-9) and related molecules in human monocytes. The most relevant Hz-dependent mechanisms underlying aberrant MMP-9 function in malaria are based on current evidence from in vitro models of cultured human monocytes. After Hz phagocytosis, some lipoperoxidation products generated by Hz autocatalysis such as 15-HETE can promote early and late activation of PKC and p38 MAPK. These kinases have been associated with cytosolic I-kBα phosphorylation and degradation, resulting in subsequent nuclear translocation of NF-kB p50 and p65 subunits. Consequently, the transcription and protein expression of several pro-inflammatory molecules including TNF-α, IL-1β, and MIP-1α, and of some proteolytic enzymes or inhibitors such as lysozyme, pro-MMP-9, and TIMP-1 is enhanced. p38 MAPK can also promote monocyte degranulation, releasing pro-MMP-9, TIMP-1 and lysozyme into the extracellular environment. After secretion of these molecules, several proteolytic events can occur. Active MMP-9, generated from MMP-3 processing of the pro-enzyme, can further modulate TNF-α shedding from cell membrane in a similar manner as TACE, whereas ICE activates IL-1β after cleaving its pro-peptide. Soluble TNF-α, IL-1β, and MIP-1α have been shown to play a key role in mediating Hz effects on MMP-9, lysozyme, and TIMP-1 production, possibly generating some auto-enhancing loops. Hz-enhanced MMP-9 could favour CM development through complementary proteolytic activities (see Figure 5). On the other hand, TIMP-1 is primarily referred to as a MMP-9 inhibitor, thus TIMP-1 Hz-enhanced levels could supposedly be protective. However, several MMP-independent functions such as inhibition of cell apoptosis and growth have been recently described for TIMP-1. Thus, Hz-enhanced TIMP-1 protein may play a role in prolonged survival of impaired Hz-fed monocytes, in their altered maturation to dendritic cells and in their reduced ability to coordinate erythropoiesis. Finally, enhanced plasma levels of human lysozyme have been depicted as a risk factor for severe malaria.