Title:
Extracellular matrix metalloproteinase inducer shows active perivascular cuffs in multiple sclerosis.

Abstract:
Inflammatory perivascular cuffs are comprised of leucocytes that accumulate in the perivascular space around post-capillary venules before their infiltration into the parenchyma of the central nervous system. Inflammatory perivascular cuffs are commonly found in the central nervous system of patients with multiple sclerosis and in the animal model experimental autoimmune encephalomyelitis. Leucocytes that accumulate in the perivascular space secrete matrix metalloproteinases that aid their transmigration into the neural parenchyma. We described previously that the upstream inducer of matrix metalloproteinase expression, extracellular matrix metalloproteinase inducer (CD147), was elevated in experimental autoimmune encephalomyelitis, and that its inhibition reduced leucocyte entry into the central nervous system. Here we investigated whether the expression of extracellular matrix metalloproteinase inducer varies with the temporal evolution of lesions in murine experimental autoimmune encephalomyelitis, whether it was uniformly upregulated across multiple sclerosis specimens, and whether it was a feature of inflammatory perivascular cuffs in multiple sclerosis lesions. In experimental autoimmune encephalomyelitis, elevation of extracellular matrix metalloproteinase inducer was correlated with the appearance and persistence of clinical signs of disease. In both murine and human samples, extracellular matrix metalloproteinase inducer was detected on endothelium in healthy and disease states but was dramatically increased in and around inflammatory perivascular cuffs on leucocytes, associated with matrix metalloproteinase expression, and on resident cells including microglia. Leucocyte populations that express extracellular matrix metalloproteinase inducer in multiple sclerosis lesions included CD4+ and CD8+ T lymphocytes, B lymphocytes and monocyte/macrophages. The extra-endothelial expression of extracellular matrix metalloproteinase inducer was a marker of the activity of lesions in multiple sclerosis, being present on leucocyte-containing perivascular cuffs but not in inactive lesions. By using a function-blocking antibody, we implicate extracellular matrix metalloproteinase inducer in the adhesion of leucocytes to endothelial cells and determined that its activity was more crucial on leucocytes than on endothelium in leucocyte-endothelial cell engagement in vitro. Extracellular matrix metalloproteinase inducer activity regulated the level of alpha 4 integrin on leucocytes through a mechanism associated with nuclear factor κB signalling. Blocking extracellular matrix metalloproteinase inducer attenuated the transmigration of monocytes and B lymphocytes across a model of the blood-brain barrier in culture. In summary, we describe the prominence of extracellular matrix metalloproteinase inducer in central nervous system inflammatory perivascular cuffs, emphasize its dual role in matrix metalloproteinase induction and leucocyte adhesion, and highlight the elevation of extracellular matrix metalloproteinase inducer as an orchestrator of the infiltration of leucocytes into the central nervous system parenchyma.