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 kB 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...

Impact of Minocycline on Extracellular Matrix Metalloproteinase Inducer, a Factor Implicated in Multiple Sclerosis Immunopathogenesis

“…A pathogenic role for EMMPRIN in the inflammatory cascades in MS is suggested by its functions in regulating T cell activation and proliferation (5-7), and by the reports that EMMPRIN promotes the migration (8, 9), adhesion (10,11), and barrier-crossing properties (12, 13) of leukocytes. In support, inflammatory perivascular cuffs in the CNS of EAE and MS specimens have highly elevated EMMPRIN expression in many leukocyte subsets (11), and mice treated with anti-EMMPRIN Abs have reduced EAE clinical severity (12,20).…”

“…In support, inflammatory perivascular cuffs in the CNS of EAE and MS specimens have highly elevated EMMPRIN expression in many leukocyte subsets (11), and mice treated with anti-EMMPRIN Abs have reduced EAE clinical severity (12,20). To further ascribe importance to EMMPRIN in MS, we evaluated whether established or emerging therapies in MS affect EMMPRIN expression in leukocytes.…”

“…Treatment with anti-EMMPRIN Abs reduced EAE clinical severity, the number of perivascular cuffs, and MMP activity (12,20). Perivascular cuffs, which are aggregates of immune cells in the perivascular space of postcapillary venules prior to their entry into the CNS parenchyma, were shown to be enriched for EMMPRIN expression that colocalized with T cells, B cells, and macrophages, and with manifestation of MMP activity (11). In vitro, treatments with an anti-EMMPRIN Ab reduced the adhesion and migration of leukocytes across blood-brain barrier endothelial cells (11), as well as T cell neurotoxicity (12).…”

“…MS is an immune-mediated disorder of the CNS characterized by the generation of myelin-reactive T cells, demyelination, and axonal degeneration. Accumulating evidence supports functional roles for EMMPRIN during T cell activation and proliferation (5-7), migration (8,9), adhesion (10,11), and invasion (12,13), all steps important in the pathogenesis of MS as well as other immunological diseases (1). Although it is unclear how all these mechanisms connect, it is supported by the identification of several EMMPRIN-interacting proteins that correspond to these functions such as monocarboxylate transporters (MCTs) (14,15), integrins (16), CD98 (17), cyclophilins (18), and EMMPRIN itself (1,19).…”

“…Perivascular cuffs, which are aggregates of immune cells in the perivascular space of postcapillary venules prior to their entry into the CNS parenchyma, were shown to be enriched for EMMPRIN expression that colocalized with T cells, B cells, and macrophages, and with manifestation of MMP activity (11). In vitro, treatments with an anti-EMMPRIN Ab reduced the adhesion and migration of leukocytes across blood-brain barrier endothelial cells (11), as well as T cell neurotoxicity (12). Thus, therapies that dampen down EMMPRIN levels would likely be beneficial in hindering various T cell activities in MS.…”