title: Lipocalin-2 is increased in progressive multiple sclerosis and inhibits remyelination.
abstract: OBJECTIVE
  We aimed to examine the regulation of lipocalin-2 (LCN2) in multiple sclerosis (MS) and its potential functional relevance with regard to myelination and neurodegeneration.
  
  
  METHODS
  We determined LCN2 levels in 3 different studies: (1) in CSF and plasma from a case-control study comparing patients with MS (n = 147) with controls (n = 50) and patients with relapsing-remitting MS (n = 75) with patients with progressive MS (n = 72); (2) in CSF and brain tissue microdialysates from a case series of 7 patients with progressive MS; and (3) in CSF at baseline and 60 weeks after natalizumab treatment in a cohort study of 17 patients with progressive MS. Correlation to neurofilament light, a marker of neuroaxonal injury, was tested. The effect of LCN2 on myelination and neurodegeneration was studied in a rat in vitro neuroglial cell coculture model.
  
  
  RESULTS
  Intrathecal production of LCN2 was increased predominantly in patients with progressive MS (p < 0.005 vs relapsing-remitting MS) and displayed a positive correlation to neurofilament light (p = 0.005). Levels of LCN2 in brain microdialysates were severalfold higher than in the CSF, suggesting local production in progressive MS. Treatment with natalizumab in progressive MS reduced LCN2 levels an average of 13% (p < 0.0001). LCN2 was found to inhibit remyelination in a dose-dependent manner in vitro.
  
  
  CONCLUSIONS
  LCN2 production is predominantly increased in progressive MS. Although this moderate increase does not support the use of LCN2 as a biomarker, the correlation to neurofilament light and the inhibitory effect on remyelination suggest that LCN2 might contribute to neurodegeneration through myelination-dependent pathways.
authors.affiliation: Neuroimmunology Unit (F.A.N., M.K., S.A., T.O., F.P.), Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Institute of Infection, Immunity and Inflammation (C.E., C.L.), University of Glasgow, UK; Department of Pharmacology and Clinical Neuroscience (J.B., A.M.D., A.S.) and Neurosurgery (T.B.), Umeå University, Sweden; and Danish Multiple Sclerosis Center (J.R.C., F.S.), Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
authors.forename: Faiez
authors.initials: F
authors.lastname: Al Nimer
authors.affiliation: Neuroimmunology Unit (F.A.N., M.K., S.A., T.O., F.P.), Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Institute of Infection, Immunity and Inflammation (C.E., C.L.), University of Glasgow, UK; Department of Pharmacology and Clinical Neuroscience (J.B., A.M.D., A.S.) and Neurosurgery (T.B.), Umeå University, Sweden; and Danish Multiple Sclerosis Center (J.R.C., F.S.), Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
authors.forename: Christina
authors.initials: C
authors.lastname: Elliott
authors.affiliation: Neuroimmunology Unit (F.A.N., M.K., S.A., T.O., F.P.), Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Institute of Infection, Immunity and Inflammation (C.E., C.L.), University of Glasgow, UK; Department of Pharmacology and Clinical Neuroscience (J.B., A.M.D., A.S.) and Neurosurgery (T.B.), Umeå University, Sweden; and Danish Multiple Sclerosis Center (J.R.C., F.S.), Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
authors.forename: Joakim
authors.initials: J
authors.lastname: Bergman
authors.affiliation: Neuroimmunology Unit (F.A.N., M.K., S.A., T.O., F.P.), Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Institute of Infection, Immunity and Inflammation (C.E., C.L.), University of Glasgow, UK; Department of Pharmacology and Clinical Neuroscience (J.B., A.M.D., A.S.) and Neurosurgery (T.B.), Umeå University, Sweden; and Danish Multiple Sclerosis Center (J.R.C., F.S.), Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Khademi
authors.affiliation: Neuroimmunology Unit (F.A.N., M.K., S.A., T.O., F.P.), Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Institute of Infection, Immunity and Inflammation (C.E., C.L.), University of Glasgow, UK; Department of Pharmacology and Clinical Neuroscience (J.B., A.M.D., A.S.) and Neurosurgery (T.B.), Umeå University, Sweden; and Danish Multiple Sclerosis Center (J.R.C., F.S.), Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Dring
authors.affiliation: Neuroimmunology Unit (F.A.N., M.K., S.A., T.O., F.P.), Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Institute of Infection, Immunity and Inflammation (C.E., C.L.), University of Glasgow, UK; Department of Pharmacology and Clinical Neuroscience (J.B., A.M.D., A.S.) and Neurosurgery (T.B.), Umeå University, Sweden; and Danish Multiple Sclerosis Center (J.R.C., F.S.), Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
authors.forename: Shahin
authors.initials: S
authors.lastname: Aeinehband
authors.affiliation: Neuroimmunology Unit (F.A.N., M.K., S.A., T.O., F.P.), Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Institute of Infection, Immunity and Inflammation (C.E., C.L.), University of Glasgow, UK; Department of Pharmacology and Clinical Neuroscience (J.B., A.M.D., A.S.) and Neurosurgery (T.B.), Umeå University, Sweden; and Danish Multiple Sclerosis Center (J.R.C., F.S.), Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
authors.forename: Tommy
authors.initials: T
authors.lastname: Bergenheim
authors.affiliation: Neuroimmunology Unit (F.A.N., M.K., S.A., T.O., F.P.), Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Institute of Infection, Immunity and Inflammation (C.E., C.L.), University of Glasgow, UK; Department of Pharmacology and Clinical Neuroscience (J.B., A.M.D., A.S.) and Neurosurgery (T.B.), Umeå University, Sweden; and Danish Multiple Sclerosis Center (J.R.C., F.S.), Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
authors.forename: Jeppe
authors.initials: J
authors.lastname: Romme Christensen
authors.affiliation: Neuroimmunology Unit (F.A.N., M.K., S.A., T.O., F.P.), Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Institute of Infection, Immunity and Inflammation (C.E., C.L.), University of Glasgow, UK; Department of Pharmacology and Clinical Neuroscience (J.B., A.M.D., A.S.) and Neurosurgery (T.B.), Umeå University, Sweden; and Danish Multiple Sclerosis Center (J.R.C., F.S.), Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
authors.forename: Finn
authors.initials: F
authors.lastname: Sellebjerg
authors.affiliation: Neuroimmunology Unit (F.A.N., M.K., S.A., T.O., F.P.), Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Institute of Infection, Immunity and Inflammation (C.E., C.L.), University of Glasgow, UK; Department of Pharmacology and Clinical Neuroscience (J.B., A.M.D., A.S.) and Neurosurgery (T.B.), Umeå University, Sweden; and Danish Multiple Sclerosis Center (J.R.C., F.S.), Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Svenningsson
authors.affiliation: Neuroimmunology Unit (F.A.N., M.K., S.A., T.O., F.P.), Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Institute of Infection, Immunity and Inflammation (C.E., C.L.), University of Glasgow, UK; Department of Pharmacology and Clinical Neuroscience (J.B., A.M.D., A.S.) and Neurosurgery (T.B.), Umeå University, Sweden; and Danish Multiple Sclerosis Center (J.R.C., F.S.), Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
authors.forename: Christopher
authors.initials: C
authors.lastname: Linington
authors.affiliation: Neuroimmunology Unit (F.A.N., M.K., S.A., T.O., F.P.), Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Institute of Infection, Immunity and Inflammation (C.E., C.L.), University of Glasgow, UK; Department of Pharmacology and Clinical Neuroscience (J.B., A.M.D., A.S.) and Neurosurgery (T.B.), Umeå University, Sweden; and Danish Multiple Sclerosis Center (J.R.C., F.S.), Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.affiliation: Neuroimmunology Unit (F.A.N., M.K., S.A., T.O., F.P.), Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Institute of Infection, Immunity and Inflammation (C.E., C.L.), University of Glasgow, UK; Department of Pharmacology and Clinical Neuroscience (J.B., A.M.D., A.S.) and Neurosurgery (T.B.), Umeå University, Sweden; and Danish Multiple Sclerosis Center (J.R.C., F.S.), Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Piehl