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

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dc.contributor.authorAllan, Euan R O
dc.contributor.authorCampden, Rhiannon I
dc.contributor.authorEwanchuk, Benjamin W
dc.contributor.authorTailor, Pankaj
dc.contributor.authorBalce, Dale R
dc.contributor.authorMcKenna, Neil T
dc.contributor.authorGreene, Catherine J
dc.contributor.authorWarren, Amy L
dc.contributor.authorReinheckel, Thomas
dc.contributor.authorYates, Robin M
dc.date.accessioned2018-09-26T12:06:07Z
dc.date.available2018-09-26T12:06:07Z
dc.date.issued2017-05-10
dc.date.updated2018-09-26T12:06:07Z
dc.description.abstractAbstract Background Hypomethylation 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. Methods Experimental 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. Results We 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. Conclusion Together, these data support a novel role for cathepsin Z in the propagation of IL-1β-driven neuroinflammation.
dc.identifier.citationJournal of Neuroinflammation. 2017 May 10;14(1):103
dc.identifier.doihttps://doi.org/10.1186/s12974-017-0874-x
dc.identifier.urihttp://hdl.handle.net/1880/107968
dc.language.rfc3066en
dc.rights.holderThe Author(s).
dc.titleA role for cathepsin Z in neuroinflammation provides mechanistic support for an epigenetic risk factor in multiple sclerosis
dc.typeJournal Article
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