Persistent macrophage/microglial activation and myelin disruption after experimental autoimmune encephalomyelitis in tissue inhibitor of metalloproteinase-1-deficient mice.
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.
Crocker
Stephen J
SJ
The Molecular and Integrative Neurosciences Department, The Scripps Research Institute, SP30-2110, 10550 North Torrey Pines Rd., La Jolla, CA 92037, USA. crocker@scripps.edu
Whitmire
Jason K
JK
Frausto
Ricardo F
RF
Chertboonmuang
Parntip
P
Soloway
Paul D
PD
Whitton
J Lindsay
JL
Campbell
Iain L
IL
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D003711:Demyelinating Diseases / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000503:physiopathology; D007114:Immunization; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology*; D009185:Myelin Proteins; D009186:Myelin Sheath / Q000378:metabolism*; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D020556:Neutrophil Infiltration; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D019715:Tissue Inhibitor of Metalloproteinase-1