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(American Journal of Pathology. 2006;169:2104-2116.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060626

Persistent Macrophage/Microglial Activation and Myelin Disruption after Experimental Autoimmune Encephalomyelitis in Tissue Inhibitor of Metalloproteinase-1-Deficient Mice

Stephen J. Crocker*, Jason K. Whitmire*, Ricardo F. Frausto*, Parntip Chertboonmuang*, Paul D. Soloway{dagger}, J. Lindsay Whitton* and Iain L. Campbell*{ddagger}

From the Molecular and Integrative Neurosciences Department,* The Scripps Research Institute, La Jolla, California; the Division of Nutritional Sciences,{dagger} College of Agriculture and Life Sciences, Cornell University, Ithaca, New York; and the School of Molecular and Microbial Biosciences,{ddagger} University of Sydney, Sydney, Australia

Increased leukocyte trafficking into the parenchyma during inflammatory responses in the central nervous system (CNS) is facilitated by the extracellular proteolytic activities of matrix metalloproteinases that are regulated, in part, by the endogenous tissue inhibitors of metalloproteinases (TIMPs). In experimental autoimmune encephalomyelitis (EAE), TIMP-1 gene expression is induced in astrocytes surrounding inflammatory lesions in the CNS. The physiological importance of this temporal and spatial relationship is not clear. Herein, we have addressed the functional role of TIMP-1 in a myelin oligodendrocyte glycoprotein (MOG35-55)-induced model of EAE using TIMP-1-deficient (TIMP-1–/–) C57BL/6 mice. Although CD4+ T-cell immune responses to myelin in wild-type (WT) and TIMP-1–/– mice were similar, analysis of CNS tissues from TIMP-1–/– mice after EAE revealed more severe myelin pathology than that of WT mice. This disruption of myelin was associated with both increased lymphocyte infiltration and microglial/macrophage accumulation in the brain parenchyma. These findings suggest that induction of TIMP-1 by astrocytes during EAE in WT mice represents an inherent cytoprotective response that mitigates CNS myelin injury through the regulation of both immune cell infiltration and microglial activation.




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