Local inhibition of matrix metalloproteinases reduced M2 macrophage activity and impeded recovery in spinal cord transected rats after treatment with fibroblast growth factor-1 and nerve grafts

摘要

Alternatively activated macrophages (M2 macrophages) promote central nervous system regeneration.Our previous study demonstrated that treatment with peripheral nerve grafts and fibroblast growth factor-1 recruited more M2 macrophages and improved partial functional recovery in spinal cord transected rats.The migration of macrophages is matrix metalloproteinase (MMP) dependent.We used a general inhibitor of MMPs to influence macrophage migration,and we examined the migration of macrophage populations and changes in spinal function.Rat spinal cords were completely transected at T8,and 5 mm of spinal cord was removed (group T).In group R,spinal cord-transected rats received treatment with fibroblast grow th factor-1and peripheral nerve grafts.In group RG,rats received the same treatment as group R with the addition of 200 μM GM6001 (an MMP inhibitor) to the fibrin mix.We found that MMP-9,but not MMP-2,was upregulated in the graft area of rats in group R.Local application of the MMP inhibitor resulted in a reduction in the ratio of arginase-1 (M2 macrophage subset)/inducible nitric oxide synthase-postive cells.When the MMP inhibitor was applied at 8 weeks postoperation,the partial functional recovery observed in group R was lost.This effect was accompanied by a decrease in brain-derived neurotrophic factor levels in the nerve graft.These results suggested that the arginase-1 positive population in spinal cord transected rats is a migratory cell population rather than the phenotypic conversion of early iNOS+ cells and that the migration of the arginase-l+ population could be regulated locally.Simultaneous application of MMP inhibitors or promotion of MMP activity for spinal cord injury needs to be considered if the coadministered treatment involves M2 recruitment.