Fibronectin- and Vitronectin-Induced Microglial Activation and Matrix Metalloproteinase-9 Expression Is Mediated by Integrins α5β1 and αvβ5

Abstract

Early in the pathogenesis of multiple sclerosis, the blood-brain barrier is compromised, which leads to deposition of the plasma proteins fibronectin and vitronectin in cerebral parenchyma. In light of our previous finding that microglial activation in vitro is strongly promoted by fibronectin and vitronectin, we set out to examine the possibility that modulation of microglial activation by fibronectin or vitronectin is an important regulatory mechanism in vivo. In an experimental autoimmune encephalomyelitis mouse model of demyelination, total brain levels of fibronectin and vitronectin were strongly increased and there was a close relationship between fibronectin and vitronectin deposition, microglial activation, and microglial expression of matrix metalloproteinase-9. In murine cell culture, flow cytometry for MHC class I and gelatin zymography revealed that microglial activation and expression of pro-matrix metalloproteinase-9 were significantly increased by fibronectin and vitronectin. Function-blocking studies showed that the influence of fibronectin and vitronectin was mediated by the α5β1 and αvβ5 integrins, respectively. Taken together, this work suggests that fibronectin and vitronectin deposition during demyelinating disease is an important influence on microglial activation state. Furthermore, it provides the first evidence that the α5β1 and αvβ5 integrins are important mediators of microglial activation.

Astrocyte reactivity after brain injury—: The role of galectins 1 and 3

“…Gal‐1‐induced apoptosis involves several intracellular mediators including the transcription factor AP1 and the downregulation of Bcl2 protein production (Hahn et al, 2004; Rabinovich et al, 2000; Walzel et al, 2000). Taking into account that α5β1 integrin is an important mediator of microglial activation (Milner et al, 2007), cell surface presentation of Gal‐1 may be implicated in the α5β1‐integrin signaling also leading to death of microglia, consistent with our in vitro observations. Thus, Gal‐1 addition reduces the number of microglia, the vast majority of glial cells in the cultures of reactive glia isolated from the stab wound injured cerebral cortex, likely by both reducing their activation and proliferation as well as their survival.…”

Molecular Mechanisms of Glioma Cell Motility

“…MMP-2 and MMP-9 convert latent pro-migratory transforming growth factor (TGF)-β into its active form, which in turn induces MMP-2 in a feedback loop (see the section "The Role of TGF-β in Glioma Cell Motility" (45-47)). MMP-9 expression or activity can be regulated by: activation of signal transducer and activator of transcription (STAT)3; epidermal growth factor (EGF); FN; vitronectin (VN); interleukin (IL)-1β; tumor necrosis factor (TNF)-a; and TGF-β (47)(48)(49)(50)(51)(52). Furthermore, glioma cells exploit MMP-14 that is expressed by surrounding microglia cells (53).…”

Increased expression of fibronectin and the α5β1 integrin in angiogenic cerebral blood vessels of mice subject to hypobaric hypoxia

“…For protein quantification, gels were scanned using a Bio-Rad VersaDoc imaging system (Hercules, CA) and band intensities quantified using the NIH image program. Within each brain sample, levels of fibronectin and the α5 or α1 integrins were first normalised to the level of β-actin, and then expressed as the fold-increase over the level present within the brain of normoxic animals, as described previously (Milner et al, 2007a). Hypoxic-induced changes in brain capillary density, as assessed by CD31 immunohistochemistry.…”