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A role for cathepsin Z in neuroinflammation provides mechanistic support for an epigenetic risk factor in multiple sclerosis

  • Allan, Euan R. O.1
  • Campden, Rhiannon I.1, 2
  • Ewanchuk, Benjamin W.1, 2
  • Tailor, Pankaj2
  • Balce, Dale R.1, 2
  • McKenna, Neil T.1, 2
  • Greene, Catherine J.1, 2
  • Warren, Amy L.3
  • Reinheckel, Thomas4, 5
  • Yates, Robin M.1, 2
  • 1 University of Calgary, Snyder Institute for Chronic Disease, Calgary, AB, T2N 4 N1, Canada , Calgary (Canada)
  • 2 University of Calgary, Department of Biochemistry and Molecular Biology, Faculty of Medicine, 3330 Hospital Drive NW, HRIC 4AA10, Calgary, AB, T2N 4 N1, Canada , Calgary (Canada)
  • 3 University of Calgary, Department of Veterinary Clinical and Diagnostic Services, Faculty of Veterinary Medicine, Calgary, AB, T2N 4 N1, Canada , Calgary (Canada)
  • 4 Albert-Ludwigs-University, Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Freiburg, D-79104, Germany , Freiburg (Germany)
  • 5 Albert-Ludwigs-University, BIOSS Centre for Biological Signalling Studies, Freiburg, D-79104, Germany , Freiburg (Germany)
Published Article
Journal of Neuroinflammation
Springer (Biomed Central Ltd.)
Publication Date
May 10, 2017
DOI: 10.1186/s12974-017-0874-x
Springer Nature


BackgroundHypomethylation of the cathepsin Z locus has been proposed as an epigenetic risk factor for multiple sclerosis (MS). Cathepsin Z is a unique lysosomal cysteine cathepsin expressed primarily by antigen presenting cells. While cathepsin Z expression has been associated with neuroinflammatory disorders, a role for cathepsin Z in mediating neuroinflammation has not been previously established.MethodsExperimental autoimmune encephalomyelitis (EAE) was induced in both wildtype mice and mice deficient in cathepsin Z. The effects of cathepsin Z-deficiency on the processing and presentation of the autoantigen myelin oligodendrocyte glycoprotein, and on the production of IL-1β and IL-18 were determined in vitro from cells derived from wildtype and cathepsin Z-deficient mice. The effects of cathepsin Z-deficiency on CD4+ T cell activation, migration, and infiltration to the CNS were determined in vivo. Statistical analyses of parametric data were performed by one-way ANOVA followed by Tukey post-hoc tests, or by an unpaired Student’s t test. EAE clinical scoring was analyzed using the Mann–Whitney U test.ResultsWe showed that mice deficient in cathepsin Z have reduced neuroinflammation and dramatically lowered circulating levels of IL-1β during EAE. Deficiency in cathepsin Z did not impact either the processing or the presentation of MOG, or MOG- specific CD4+ T cell activation and trafficking. Consistently, we found that cathepsin Z-deficiency reduced the efficiency of antigen presenting cells to secrete IL-1β, which in turn reduced the ability of mice to generate Th17 responses—critical steps in the pathogenesis of EAE and MS.ConclusionTogether, these data support a novel role for cathepsin Z in the propagation of IL-1β-driven neuroinflammation.

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