Lack of TIMP-1 increases severity of experimental autoimmune encephalomyelitis: Effects of darbepoetin alfa on TIMP-1 null and wild-type mice

Michael Thorne, Craig S. Moore, George S. Robertson

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

Abstract

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) are both characterized by the infiltration of myelin-reactive T cells that trigger oligodendrocyte death associated with axonal loss and neurodegeneration in the CNS. Proteolysis of the cerebral vascular extracellular matrix (ECM) resulting in blood-brain barrier (BBB) breakdown is thought to facilitate infiltration of autoreactive T cells in both of these demyelinating disorders. Increased matrix metalloprotease (MMP) activity coupled with reduced levels of tissue inhibitor of metalloproteases (TIMPs) contribute to a loss of BBB integrity. Erythropoietin induces expression of TIMP-1 in endothelial cells suggesting this property may account in part for its ability to maintain BBB integrity and efficacy in a preliminary clinical MS trial. Consistent with this hypothesis, we report here that administration of the erythropoietin analogue darbepoetin alfa at a low dose that did not elevate hematocrit reduced EAE severity in female C57BL/6 mice when administered following the onset of clinical signs. The protective effects of darbepoetin alfa were associated with an increase in the number of astrocytes expressing TIMP-1 in the brain and spinal cord. In keeping with a central role for TIMP-1 in this autoimmune model of acute demyelination, TIMP-1 null mice displayed a more severe EAE phenotype than wild-type littermates. Interestingly, we observed a lack of effect of darbepoetin alfa on EAE severity in TIMP-1 null mice. These findings indicate that TIMP-1 deficiency both enhances disease severity and attenuates the beneficial effects of low dose darbepoetin alfa in a mouse model of EAE. Crown

Original languageEnglish
Pages (from-to)92-100
Number of pages9
JournalJournal of Neuroimmunology
Volume211
Issue number1-2
DOIs
Publication statusPublished - Jun 25 2009

Bibliographical note

Funding Information:
The authors are grateful to Drs. Lindsay Whitton and Iain Campbell for generously providing Timp-1 (−/−) mice and Dr. Stephen J. Crocker for his useful comments during preparation of this manuscript. The authors gratefully acknowledge Elizabeth Belland, Kay Murphy and Purnima Narayanan for excellent technical support. This work was funded in part by a grant from the MS Society of Canada. MT was supported by a Nova Scotia Health Research Foundation Master's Award.

ASJC Scopus Subject Areas

  • Immunology and Allergy
  • Immunology
  • Neurology
  • Clinical Neurology

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