title: Suppression of NK and CD8+T cells reduces astrogliosis but accelerates cerebellar dysfunction and shortens life span in a mouse model of Sandhoff disease.
abstract: Sandhoff disease is an inherited lysosomal storage disease, resulting from the deficiency of lysosomal β-hexosaminidase A and B enzyme activity. The Hexb-/- mouse model recapitulates human disease and leads to fatal neurodegeneration and neuroinflammation. IL-15 is important for the proliferation of NK, NK T, and CD8+cytotoxic/memory T cells. In order to determine how changes to IL-15-dependent immune cell populations would alter the course of Sandhoff disease in mice, we generated a Hexb-/-Il-15-/- double knockout mouse and used motor behaviour tests, analyzed peripheral blood and brain leukocyte immunophenotypes, cytokine secretion, as well as examined markers of microgliosis, astrogliosis and apoptosis. Hexb-/-Il-15-/- mice had an accelerated neurodegenerative phenotype, and reached the humane endpoint at 118±3.5d, compared to Hexb-/- mice (127±2.2d). The performance of Hexb-/-Il-15-/- mice declined earlier than Hexb-/- mice on the rotarod and righting reflex motor behaviour tests. Hexb-/- mice had a significantly higher prevalence of pro-inflammatory monocytes in the blood relative to C57BL/6 mice, but this was unaltered by IL-15 deficiency. The prevalence of NK cells and CD8+T cells in Il-15-/- and Hexb-/-Il-15-/- mice was decreased compared to wild type and Hexb-/- mice. While Hexb-/- mice displayed an increase in the prevalence of CD4+and CD8+T cells in brain leukocytes compared to C57BL/6 mice, there was a decrease in CD8+T cells in Hexb-/-Il-15-/- compared to Hexb-/- mice. In addition, circulating IL-17 and IL-10 levels were significantly higher in Hexb-/-Il-15-/- mice, suggesting heightened inflammation compared to Hexb-/- mice. Interestingly, astrogliosis levels were significantly reduced in the cerebellum of Hexb-/-Il-15-/- mice compared to Hexb-/- mice while microgliosis was not affected in brains of Hexb-/-Il-15-/- mice. Our study demonstrated that IL-15 depletion dramatically reduced numbers of NK and CD8+T cells as well as astrocytes but accelerated disease progression in Sandhoff mice. These results pointed to interactions between NK/CD8+T cells and astrogliosis and potentially a protective role for NK/CD8+T cells and/or astrocytes during disease progression. This observation supports the notion that expanding the IL-15-dependent NK and CD8+T cells populations with IL-15 therapy may have therapeutic benefits for Sandhoff disease.
authors.affiliation: Department of Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: White
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada; Thrombosis and Atherosclerosis Research Institute McMaster University, Hamilton, Ontario, Canada.
authors.forename: Bernardo L
authors.initials: BL
authors.lastname: Trigatti
authors.affiliation: Department of Biology, McMaster University, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. Electronic address: igdoura@mcmaster.ca.
authors.forename: Suleiman A
authors.initials: SA
authors.lastname: Igdoura
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002526:Cerebellar Diseases / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000628:therapy*; D054819:Hexosaminidase B / Q000235:genetics / Q000378:metabolism; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism / Q000473:pathology*; D008124:Locomotion / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000209:etiology / Q000235:genetics; D012497:Sandhoff Disease / Q000150:complications* / Q000235:genetics / Q000401:mortality*
chemical_list: D015703:Antigens, CD; D005904:Glial Fibrillary Acidic Protein; D019409:Interleukin-15; C528900:glial fibrillary astrocytic protein, mouse; D054819:Hexosaminidase B
keywords: Il-15; Lymphocytes; Neurodegeneration; Neuroinflammation; Sandhoff disease