elevated matrix metalloproteinase (MMP) in an animal model of multiple sclerosis is protective by affecting Th1/Th2 polarization

ABSTRACTInflammation in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), is manifested by changes in matrix metalloproteinase (MMP) expression and in the ratio of T helper (Th) 1 and 2 effector cytokines. Here, we provide a comprehensive documentation of MMPs in EAE and report that of all the MMPs that could be measured at peak disease in spinal cord tissue, MMP‐12 was the most highly up‐regulated. In contrast to previously published findings of MMPs in EAE, this increase in MMP‐12 expression was associated with protection, as MMP‐12 null mice had significantly worse maximum severity and EAE disease burden compared with wild‐type (WT) controls. When spleen and lymph node cells were removed from EAE‐afflicted WT and MMP‐12 null mice at the same disease score before divergence of disease and restimulated in vitro, the MMP‐12 null cells had significantly higher Th1 to Th2 cytokine ratio. Measurements of the transcriptional regulators of T cell polarization revealed that MMP‐12 null cells had increased T‐bet and reduced GATA‐3 expression, a condition that favors a Th1 bias. These results emphasize that specific MMPs can have beneficial roles in inflammation, and they implicate MMPs in T effector polarization for the first time.