Increased cerebrospinal fluid metalloproteinase-2 and interleukin-6 are associated with albumin quotient in neuromyelitis optica: Their possible role on blood-brain barrier disruption

Mult Scler. 2017 Jul;23(8):1072-1084. doi: 10.1177/1352458516672015. Epub 2016 Sep 28.


Background: Inflammation in neuromyelitis optica (NMO) is triggered by a serum antibody against the aquaporin-4 (AQP4). This process requires antibody penetration of the blood-brain barrier (BBB), but the mechanisms for BBB disruption in NMO remain unknown.

Objective: We examined whether changes in cerebrospinal fluid (CSF) and serum matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and cytokines are associated with BBB disruption in NMO.

Methods: The concentrations 9 MMPs, 4 TIMPs, and 14 cytokines were measured by multiplex assay in CSF and serum samples from 29 NMO patients, 29 relapsing-remitting multiple sclerosis (MS) patients, and 27 patients with other neurological disorders. We also performed immunohistochemistry for MMP-2 and TIMP-1 expression in post-mortem brain tissues from NMO patients.

Results: NMO patients exhibited significantly elevated MMP-2, TIMP-1, interleukin-6, and MMP-2/TIMP-2 ratio in CSF (but not sera) than the other groups. The CSF/serum albumin ratio, an index of BBB permeability, was most strongly correlated with CSF MMP-2 concentration, which in turn correlated with CSF interleukin-6 levels. Immunohistochemistry revealed MMP-2- and TIMP-1-positive cells surrounding vessels in NMO lesions.

Conclusion: In NMO, increased CSF MMP-2, likely induced by interleukin-6 signaling, may disrupt the BBB and enable serum anti-AQP-4 antibodies migration into the central nervous system (CNS).

Keywords: Neuromyelitis optica; blood–brain barrier; matrix metalloproteinases; tissue inhibitors of metalloproteinases.

MeSH terms

  • Adult
  • Albumins / cerebrospinal fluid*
  • Aquaporin 4 / cerebrospinal fluid
  • Aquaporin 4 / immunology
  • Autoantibodies / cerebrospinal fluid
  • Blood-Brain Barrier*
  • Female
  • Humans
  • Interleukin-6 / cerebrospinal fluid*
  • Male
  • Matrix Metalloproteinase 2 / cerebrospinal fluid*
  • Middle Aged
  • Neuromyelitis Optica / cerebrospinal fluid*
  • Neuromyelitis Optica / pathology


  • Albumins
  • Aquaporin 4
  • Autoantibodies
  • IL6 protein, human
  • Interleukin-6
  • MMP2 protein, human
  • Matrix Metalloproteinase 2