A role for cathepsin Z in neuroinflammation provides mechanistic support for an epigenetic risk factor in multiple sclerosis
| العنوان: | A role for cathepsin Z in neuroinflammation provides mechanistic support for an epigenetic risk factor in multiple sclerosis |
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| المؤلفون: | Dale R. Balce, Amy L. Warren, Neil McKenna, Rhiannon I. Campden, Benjamin W. Ewanchuk, Thomas Reinheckel, Catherine J. Greene, Pankaj Tailor, Euan R.O. Allan, Robin M. Yates |
| المصدر: | Journal of Neuroinflammation Journal of Neuroinflammation, Vol 14, Iss 1, Pp 1-11 (2017) |
| بيانات النشر: | Springer Science and Business Media LLC, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | CD4-Positive T-Lymphocytes, 0301 basic medicine, Interleukin-1beta, Chemokine CXCL9, lcsh:RC346-429, Mice, Phagosomes, Leukocytes, biology, Inflammasome Activation, General Neuroscience, Experimental autoimmune encephalomyelitis, Interleukin-18, medicine.anatomical_structure, Spinal Cord, Neurology, Experimental Autoimmune Encephalomyelitis, Multiple Sclerosis, Encephalomyelitis, Autoimmune, Experimental, Experimental Autoimmune Encephalomyelitis Induction, T cell, Immunology, Short Report, Antigen-Presenting Cells, Mice, Transgenic, Myelin oligodendrocyte glycoprotein, 03 medical and health sciences, Cellular and Molecular Neuroscience, Antigen, Antigens, CD, medicine, Animals, Antigen-presenting cell, lcsh:Neurology. Diseases of the nervous system, Neuroinflammation, Cathepsin, Epilepsy, Macrophages, Cathepsin Z, medicine.disease, Molecular biology, Peptide Fragments, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, biology.protein, Myelin-Oligodendrocyte Glycoprotein, NLRP3 Inflammasome |
| الوصف: | 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. Electronic supplementary material The online version of this article (doi:10.1186/s12974-017-0874-x) contains supplementary material, which is available to authorized users. |
| تدمد: | 1742-2094 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::280501666f3773eb272a6ab9458cf27f https://doi.org/10.1186/s12974-017-0874-x |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....280501666f3773eb272a6ab9458cf27f |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 17422094 |
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