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

Inflammation 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.