Matrix metalloproteinases, tissue inhibitors of MMPs and TACE in experimental cerebral malaria

Abstract

Cerebral malaria (CM) is a life-threatening disorder and a major medical problem in developing countries. It is caused by the sequestration of malaria-infected erythrocytes onto brain endothelia, followed by blood-brain barrier (BBB) damage and neurological deficit. In the present study, matrix metalloproteinases (MMPs) were analysed in a mouse model of CM with Plasmodium berghei ANKA. Increased numbers of gelatinase B (MMP-9)-positive cells, which were also CD11b(+), were detected in the brain. In addition, activation of gelatinase B occurred in CM brains, and not in brains of mice with non-CM. However, selective genetic knockout of gelatinase B did not alter the clinical evolution of experimental CM. To study other protease balances, the mRNA expression levels of nine matrix metalloproteinases (MMPs), five membrane-type MMPs, TNF-alpha converting enzyme (TACE) and the four tissue inhibitors of metalloproteinases (TIMPs) were analysed during CM in different organs. Significant alterations in expression were observed, including increases of the mRNAs of MMP-3, -8, -13 and -14 in the spleen, MMP-8, -12, -13 and -14 in the liver and MMP-8 and -13 in the brain. Net gelatinolytic activity, independent of gelatinase B and inhibitable with EDTA, was detected in situ in the endothelia of blood vessels in CM brains, but not in brains of mice with non-CM, suggesting that metalloproteases, different from gelatinase B, are active in the BBB environment in CM. The increase in MMP expression in the brain was significantly less pronounced after infection of C57Bl/6 mice with the noncerebral strain P. berghei NK65, but it was similar in CM-susceptible C57Bl/6 and CM-resistant Balb/C mice upon infection with P. berghei ANKA. Furthermore, in comparison with C57Bl/6 mice, a larger increase in TIMP-1 and a marked, >30-fold induction in MMP-3 were found in the brains of Balb/C mice, suggesting possible protective roles for TIMP-1 and MMP-3.

Involvement of Inflammatory Chemokines in Survival of Human Monocytes Fed with Malarial Pigment

“…MCP-1 expression appears to be an important component of monocyte extravasation through the vascular endothelium (14,69), suggesting a potential role during CM, the encephalopathy caused by massive sequestration of parasitized RBCs in the brain capillaries and associated with elevated plasma TNF-␣ levels, disruption of endothelial intercellular junctions and basal lamina, ring hemorrhages, and Dürck's granulomas infiltrated with macrophages (1,31,15,41,61). Since cleavage of IL-8 (as well as ENA-78) proform by MMP-9 is required for chemokine activation (65,67) and MMP-9 involvement in CM has been proposed recently (49,66), the role of HZ-enhanced MMP-9 effects on chemokine proform processing should be considered in future studies on CM.…”

Matrix metalloproteinases 2 and 9 in rabbits with doxorubicin-induced cardiomyopathy

“…Also, Van den Steen and colleagues reported that activated forms of MMP 9 are rarely observed owing to its high instability and fast turnover. When detected, however, the active form is likely indicative of a continuous state of MMP 9 activation (Van den Steen et al 2006). The pro-forms of both enzymes documented in this study behaved in an inverse fashion, i.e., the plasma activity of , LA/Ao = left atrium-to-aorta ratio, E m /A m = mitral E-to-mitral A wave ratio, IVRT = isovolumic relaxation time, E m /IVRT = ratio between mitral E wave and isovolumic relaxation time, E sep /A sep = ratio between mitral annular diastolic velocities at the septal site, S sep = mitral annular systolic velocity at the septal site, E m /E sep = ratio between mitral E wave and mitral annular early diastolic velocity at the septal site, E lat /A lat = ratio between mitral annular diastolic velocities at the lateral site, S lat = mitral annular systolic velocity at the lateral site, E m /E lat = ratio between mitral E wave and mitral annular early diastolic velocity at the lateral site.…”

The role of Vitamin D in malaria

“…Serum MMP-8 and TIM-1 levels are significantly higher in the malaria groups compared with the control groups [118]. In a mouse model of experimental cerebral malaria, significant alterations in expressions have been observed, including increases in the mRNAs of MMP-3, MMP-8, MMP-13, and MMP-14 in the spleen, MMP-8, MMP-12, MMP-3, MMP-8, MMP-13, and MMP-14 in the liver, and MMP-8 and MMP-13 in the brain [119]. However, VDR knockout mice exhibit an increased influx of inflammatory cells, increased phosphoacetylation of NF-κB (which is associated with an increase in pro-inflammatory cells), and an upregulation of MMP-2, MMP-9, and MMP-12 in their lungs [120].…”