title: Impact of Minocycline on Extracellular Matrix Metalloproteinase Inducer, a Factor Implicated in Multiple Sclerosis Immunopathogenesis.
abstract: Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a transmembrane glycoprotein that is upregulated on leukocytes in active lesions in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Administration of anti-EMMPRIN Abs reduces the severity of EAE. Minocycline is a tetracycline antibiotic with immune-modulatory properties that decreases the severity of EAE; it was recently found to attenuate the conversion from a first demyelinating event to clinically definite MS in a phase III trial. We investigated whether and how minocycline affects the expression of EMMPRIN on T cells in culture and in mice afflicted with EAE. EMMPRIN expression in cultures of mouse splenocytes or human PBMCs was elevated upon polyclonal T cell activation, and this was reduced by minocycline correspondent with decreased P-Akt levels. An established MS medication, IFN-β, also diminished EMMPRIN levels on human cells whereas this was not readily observed for fingolimod or monomethylfumarate. In EAE-afflicted mice, minocycline treatment significantly reduced EMMPRIN levels on splenic lymphocytes at the presymptomatic (day 7) phase, and prevented the development of disease. Day 7 spleen transcripts from minocycline-treated EAE mice had a significantly lower MMP-9/TIMP-1 ratio, and significantly lower MCT-1 and CD98 levels, factors associated with EMMPRIN function. Day 16 (peak clinical severity) CNS samples from EAE mice had prominent representation of inflammatory perivascular cuffs, inflammatory molecules and EMMPRIN, and these were abrogated by minocycline. Overall, minocycline attenuated the activation-induced elevation of EMMPRIN on T cells in culture and in EAE mice, correspondent with reduced immune function and EAE CNS pathology.
authors.affiliation: Hotchkiss Brain Institute and Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Hahn
authors.affiliation: Hotchkiss Brain Institute and Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Deepak K
authors.initials: DK
authors.lastname: Kaushik
authors.affiliation: Hotchkiss Brain Institute and Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Manoj K
authors.identifier: 0000-0001-9636-4930
authors.initials: MK
authors.lastname: Mishra
authors.affiliation: Hotchkiss Brain Institute and Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Jianxiong
authors.identifier: 0000-0001-7975-4590
authors.initials: J
authors.lastname: Wang
authors.affiliation: Hotchkiss Brain Institute and Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Claudia
authors.initials: C
authors.lastname: Silva
authors.affiliation: Hotchkiss Brain Institute and Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada vyong@ucalgary.ca.
authors.forename: V Wee
authors.initials: VW
authors.lastname: Yong
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051926:Basigin / Q000235:genetics / Q000378:metabolism*; D002490:Central Nervous System / Q000187:drug effects; D017326:Clinical Trials, Phase III as Topic; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000517:prevention & control; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology; D005650:Fumarates / Q000494:pharmacology; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008298:Maleates / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008911:Minocycline / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D009000:Monocytes; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000276:immunology
chemical_list: D000900:Anti-Bacterial Agents; C497887:Bsg protein, mouse; D005650:Fumarates; D008298:Maleates; D019715:Tissue Inhibitor of Metalloproteinase-1; C073341:citraconic acid; D051926:Basigin; D016899:Interferon-beta; D020780:Matrix Metalloproteinase 9; D008911:Minocycline; D000068876:Fingolimod Hydrochloride