Fibronectin- and vitronectin-induced microglial activation and matrix metalloproteinase-9 expression is mediated by integrins alpha5beta1 and alphavbeta5.
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 alpha(5)beta(1) and alpha(v)beta(5) 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 alpha(5)beta(1) and alpha(v)beta(5) integrins are important mediators of microglial activation.
Milner
Richard
R
Department of Molecular and Experimental Medicine, The Scripps Research Institute, 20550 North Torrey Pines Road, La Jolla, CA 92037, USA. rmilner@scripps.edu
Crocker
Stephen J
SJ
Hung
Stephanie
S
Wang
Xiaoyun
X
Frausto
Ricardo F
RF
del Zoppo
Gregory J
GJ
D000818:Animals; D001921:Brain / Q000276:immunology; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D004792:Enzyme Precursors / Q000032:analysis; D005353:Fibronectins / Q000032:analysis / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000032:analysis / Q000378:metabolism; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000201:enzymology / Q000276:immunology*; D019030:Receptors, Vitronectin / Q000378:metabolism*; D019096:Vitronectin / Q000032:analysis / Q000378:metabolism*
D004792:Enzyme Precursors; D005353:Fibronectins; D015395:Histocompatibility Antigens Class I; D039081:Integrin alpha5beta1; D016023:Integrins; D019030:Receptors, Vitronectin; D019096:Vitronectin; C064660:integrin alphaVbeta5; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9