Regulation of Matrix Metalloproteinase Expression in Astrocytes, Microglia and Neurons

Abstract

In neurodegenerative disease or after brain injury, parenchymal cells in the central nervous system are activated to produce inflammatory mediators, mainly consisting of cytokine-induced factors, in a manner similar to, but clearly different from a peripheral inflammatory response. The upregulated expression of several extracellular matrix proteins in astrocytes located surrounding a neuritic plaque in Alzheimer''s disease is a good example of such a response. A family of mediators which is cytokine-induced during an inflammatory response in the periphery are the matrix metalloproteinases. Matrix metalloproteinases are calcium-requiring, zinc-containing endopeptidases that constitute a major component of the enzyme cascade responsible for degradation of extracellular matrix proteins such as collagen, proteoglycan and laminin. Little is known about the cellular source or the function of matrix metalloproteinases in the central nervous system or how their expression is regulated in brain. Thus, it was of interest to determine which factors of the so-called ''brain inflammatory response'' regulate the expression of these proteases in the nervous system. To this end, we measured the expression of matrix metalloproteinases in cultured rat astrocytes and microglia after treatment with various cytokines. Interleukin-1β, tumor necrosis factor-αand lipo-polysaccharide were potent stimulators of matrix metalloproteinase-2 (gelati-nase A) and matrix metalloproteinase-9 (gelatinase B) in cultured rat astrocytes; the effect of each secretagogue was inhibited in the presence of glucocorticoid. Interleukin-1βand lipopolysaccharide also stimulated the production of matrix metalloproteinase-3 (stromelysin-1) in astrocytes. In addition, activated microglia release matrix metalloproteinase-9. The ''coactivator'' of monocytic phagocytes, interferon-γ, rather than augmenting the response to lipopolysaccharide, inhibited it. Thus, cytokines appear to be potent regulators of matrix metalloproteinase production in astrocytes and microglia. The presence of these enzymes in ''inflamed'' central nervous system may suggest their involvement in the pathogenesis or progression of neurodegenerative diseases which are associated with an inflammatory component. Much remains to be learned about the potential substrates for these enzymes and the mechanism of their activation in the central nervous system.

Matrix Metalloproteinase-9 Gene Knock-out Protects the Immature Brain after Cerebral Hypoxia–Ischemia

“…In adult human multiple sclerosis tissue, MMP-9 has also been found expressed in activated microglia, microvessel endothelial cells, and in small numbers of astrocytes (Cuzner et al, 1996;Maeda and Sobel, 1996). Also in in vitro studies, astrocytes (Apodaca et al, 1990;Gottschall and Deb, 1996), microglia (Colton et al, 1993;Gottschall and Deb, 1996), and oligodendrocytes (Uhm et al, 1998) were shown to express MMP-9 after different treatments. In contrast to the studies in adult tissue, the present study shows MMP-9 is colocalized with microglia after neonatal HI.…”

Early Appearance of Activated Matrix Metalloproteinase-9 after Focal Cerebral Ischemia in Mice: A Possible Role in Blood—Brain Barrier Dysfunction

“…Indeed, elevated levels of proMMP-9 have been detected in the CSF of patients with multiple sclerosis (Gijbels et aI., 1992). More over, both MMP protein activity and mRNA levels are increased in rats with experimental autoimmune en cephalomyelitis (Pagenstecher et aI., 1998 proMMP-9 can be induced by tumor necrosis factor alpha in various cell types such as astrocytes (Gottschall et aI., 1995), microglial cells (Gottschall and Deb, 1996) and fibroblasts (Hanemaaijer et aI., 1993). Because of its earliness, induction of proMMP-9 at 2 hours observed in our model of focal ischemia probably cannot be attrib uted to tumor necrosis factor, which is produced mainly by leukocytes (monocytes) known to infiltrate infarcted areas later during reperfusion.…”

Astrocytes in the tempest of multiple sclerosis

“…Down-regulation of S1P1 signaling in astrocytes reduce reactive astrogliosis and improve gap-junctional communication among these cells, which might contribute to structural restoration of the CNS parenchyma in MS patients [110]. Synthetic glucorticoids have been shown to affect various inflammatory functions of astrocytes, such as cytokine synthesis [112], MMP generation [113] and GFAP-related astrocytosis [114].…”