1. A role for cathepsin Z in neuroinflammation provides mechanistic support for an epigenetic risk factor in multiple sclerosis.
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Allan, Euan R. O., Campden, Rhiannon I., Ewanchuk, Benjamin W., Tailor, Pankaj, Balce, Dale R., McKenna, Neil T., Greene, Catherine J., Warren, Amy L., Reinheckel, Thomas, and Yates, Robin M.
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MULTIPLE sclerosis risk factors , *CATHEPSINS , *METHYLATION , *ENCEPHALOMYELITIS , *EPIGENETICS , *ANIMAL experimentation , *ANTIGEN presenting cells , *ANTIGENS , *BIOLOGICAL models , *CYTOKINES , *CYTOPLASM , *DEMYELINATION , *EPILEPSY , *INTERLEUKIN-1 , *INTERLEUKINS , *LEUCOCYTES , *MACROPHAGES , *MICE , *PEPTIDES , *PROTEOLYTIC enzymes , *RESEARCH funding , *SPINAL cord , *T cells , *MEMBRANE glycoproteins , *DISEASE complications - Abstract
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. [ABSTRACT FROM AUTHOR]- Published
- 2017
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