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Fibronectin- and Vitronectin-Induced Microglial Activation and Matrix Metalloproteinase-9 Expression Is Mediated by Integrins ₅₁ and _v5¹

Richard Milner^2,*, Stephen J. Crocker, Stephanie Hung^*, Xiaoyun Wang^*, Ricardo F. Frausto and Gregory J. del Zoppo^*

^* Department of Molecular and Experimental Medicine and Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA 92037

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 ₅₁ and _v5 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 ₅₁ and _v5 integrins are important mediators of microglial activation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by a Harry Weaver Neuroscience Scholar Award from the National Multiple Sclerosis Society (to R.M.), by an Advanced Postdoctoral Fellowship from the National Multiple Sclerosis Society (to S.J.C.), and by National Institutes of Health Grants R01 NSO26945, R01 NSO38710, and R01 NSO53716.

² Address correspondence and reprint requests to Dr. Richard Milner, Department of Molecular and Experimental Medicine, MEM-132, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address: rmilner{at}scripps.edu

³ Abbreviations used in this paper: MS, multiple sclerosis; MMP, matrix metalloproteinase; ECM, extracellular matrix; EAE, experimental autoimmune encephalomyelitis; MBP, myelin basic protein; BBB, blood-brain barrier; MOG, myelin oligodendrocyte glycoprotein; GFAP, glial fibrillary acidic protein; ROI, region of interest; IF, immunofluorescence.

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