Microglial expression of alphavbeta3 and alphavbeta5 integrins is regulated by cytokines and the extracellular matrix: beta5 integrin null microglia show no defects in adhesion or MMP-9 expression on vitronectin.
As the primary immune effector cells in the CNS, microglia play a central role in regulating inflammation. The extracellular matrix (ECM) protein vitronectin is a strong inducer of microglial activation, switching microglia from a resting into an activated potentially destructive phenotype. As the activating effect of vitronectin is mediated by alphav integrins, the aim of the current study was to evaluate the requirement of the alphavbeta5 integrin in mediating microglial adhesion and activation to vitronectin, by studying these events in beta5 integrin-null murine microglia. Surprisingly, beta5 integrin null microglia were not defective in adhesion to vitronectin. Further analysis showed that microglia express the alphavbeta3 integrin, in addition to alphavbeta5. Flow cytometry revealed that microglial alphav integrin expression is regulated by cytokines and ECM proteins. alphavbeta3 integrin expression was downregulated by IFN-gamma, TNF, LPS, and TGF-beta1. alphavbeta5 expression was also reduced by IFN-gamma, TNF, and LPS, but strongly increased by the antiactivating factors TGF-beta1 and laminin. Gel zymography revealed that beta5 integrin null microglia showed no deficiency in their expression of matrix metalloproteinase (MMP)-9 in response to vitronectin. Taken together, these data show that microglia express two different alphav integrins, alphavbeta3 and alphavbeta5, and that expression of these integrins is independently regulated by cytokines and ECM proteins. Furthermore, it reveals that the alphavbeta5 integrin is not essential for mediating microglial adhesion and MMP-9 expression in response to vitronectin.
Milner
Richard
R
Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. rmilner@scripps.edu
D000818:Animals; D001921:Brain / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D015870:Gene Expression; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D019030:Receptors, Vitronectin / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism; D019096:Vitronectin / Q000378:metabolism
D016207:Cytokines; D016326:Extracellular Matrix Proteins; D039302:Integrin alphaVbeta3; D008070:Lipopolysaccharides; D019030:Receptors, Vitronectin; D053773:Transforming Growth Factor beta1; D048069:Tumor Necrosis Factors; D019096:Vitronectin; C064660:integrin alphaVbeta5; D007371:Interferon-gamma; D020780:Matrix Metalloproteinase 9