Matrix Metalloproteinase-12 Deficiency Worsens Relapsing-Remitting Experimental Autoimmune Encephalomyelitis in Association with Cytokine and Chemokine Dysregulation

The elevation of several members of the matrix metalloproteinase (MMP) family promotes the pathophysiology of both multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Nonetheless, given the multiple activities of MMPs, it remains possible that increased levels of a particular MMP may have beneficial functions during disease progression. We reported previously that MMP-12(-/-) mice of the 129/SvEv strain had a poorer ENE outcome than wild-type controls. However, we did not determine further differences in disease profiles between these groups. Using the EAE model in 129/SvEv mice, we report that disease in both wildtype and MMP-12(-/-) mice follows a relapsing-remitting course. Although both mouse groups had similar clinical onsets, subsequent relapses were more severe in MMP-12(-/-) mice; their residual disability at remission was also higher compared with wild-type controls. The worsened relapses and remissions in MMP12(-/-) mice occurred despite a deficiency of the antigen recall capacity of lymph node-derived cells as well as a reduction in the proportion of macrophages in the spinal cord during the chronic phase of EAE. Significantly, large increases of levels of chemokines and cytokines were found in the spinal cords of MMP12(-/-) mice during chronic EAE. These results highlight MMP-12 as a beneficial. enzyme in EAF and suggest that therapeutic interventions in multiple sclerosis should avoid targeting MMP-12. (Am J Pathol 2009, 174:898-909; DOI: 10.2353/ajpath.2009.080952)