Impact of minocycline and established MS medications on EMMPRIN, a new factor implicated in MS immunopathogenesis

Background: Multiple sclerosis (MS) is an immune-mediated disease directed towards the central nervous system. EMMPRIN (CD147), known as a matrix metalloproteinase (MMP) inducer, is a novel factor in MS involved in multiple immunological functions in addition to trafficking of leukocytes across the blood–brain barrier. We reported EMMPRIN to be up-regulated in leukocytes in active lesions in MS and experimental autoimmune encephalomyelitis (EAE) (Brain 136:1760, 2013). Furthermore, anti-EMMPRIN antibodies reduced the severity of EAE (J Neurosci 31:669, 2011). Objective: We investigated whether emerging or established immunomodulators used in MS affect the expression of EMMPRIN on leukocytes. We focused on minocycline, an immunomodulator that we have reported to reduce the severity of EAE in mice (Brain 125:1297, 2002), and which decreased MRI activity in a pilot trial in relapsing-remitting MS (Ann Neurol 55:756, 2004; Can J Neurol Sci 35:185, 2008). Minocycline is currently in a Phase III trial in clinically isolated syndromes (ClinicalTrials.gov Identifier: NCT00666887). Methods: Mouse splenocytes and human PBMCs were pre-incubated with or without specific immunomodulators before polyclonal T cell activation (anti-CD3, anti-CD28) in culture. Cells were analyzed for viability and EMMPRIN expression by flow cytometry, and for proliferation by tritiated thymidine incorporation. Results: EMMPRIN expression is increased upon T cell activation. Minocycline attenuated the up-regulation of EMMPRIN on activated T cells at concentrations as low as 0.5 micrograms/mL (p = 0.009 compared to no drug), without obvious effects on cell viability and proliferation. At concentrations (5–10 micrograms/ mL) of minocycline that are encountered in MS subjects on this medication, T cell expression of EMMPRIN along with proliferation and viability were lowered. Minocycline was more robust in reducing the mean fluorescence intensity of EMMPRIN, compared to percent cells with EMMPRIN. For established MS immunomodulators, interferon-beta (10-1000 U/mL) reduced EMMPRIN expression, while fingolimod (100–300 nanograms/mL) was without effect. Conclusions: An emerging (minocycline) and established (interferonbeta) MS medication attenuated the activation-induced elevation of EMMPRIN on T cells, highlighting the potential importance of EMMPRIN as a novel pathogenic factor in MS.