Lack of TIMP-1 increases severity of experimental autoimmune encephalomyelitis: Effects of darbepoetin alfa on TIMP-1 null and wild-type mice.
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.
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Michael
M
Thorne
Craig S
CS
Moore
George S
GS
Robertson
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D000068256:Darbepoetin alfa; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006397:Hematinics / Q000494:pharmacology*; D007091:Image Processing, Computer-Assisted; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013116:Spinal Cord / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*
D006397:Hematinics; D019715:Tissue Inhibitor of Metalloproteinase-1; D004921:Erythropoietin; D000068256:Darbepoetin alfa