Cystatin C Plays a Sex-Dependent Detrimental Role in Experimental Autoimmune Encephalomyelitis
Vahid Hoghooghi,
Alexandra L. Palmer,
Ariana Frederick,
Yulan Jiang,
Jessica E. Merkens,
Anjali Balakrishnan,
Trisha M. Finlay,
Anders Grubb,
Efrat Levy,
Paul Gordon,
Frank R. Jirik,
Minh Dang Nguyen,
Carol Schuurmans,
Frank Visser,
Shannon E. Dunn,
Shalina S. Ousman
Affiliations
Vahid Hoghooghi
Department of Neuroscience, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
Alexandra L. Palmer
Department of Neuroscience, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
Ariana Frederick
Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
Yulan Jiang
Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
Jessica E. Merkens
Department of Neuroscience, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
Anjali Balakrishnan
Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada
Trisha M. Finlay
Department of Neuroscience, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
Anders Grubb
Department of Clinical Chemistry, Lund University Hospital, SE 221 85 Lund, Sweden
Efrat Levy
Department of Psychiatry and Department of Biochemistry & Molecular Pharmacology, Neuroscience Institute, NYU Langone Health, New York, NY, USA; Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA
Paul Gordon
Cumming School of Medicine Centre for Health Genomics and Informatics, University of Calgary, Calgary, AB T2N 4N1, Canada
Frank R. Jirik
Department of Biochemistry & Molecular Biology, and Department of Medicine, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
Minh Dang Nguyen
Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Cell Biology & Anatomy, and Department of Biochemistry & Molecular Biology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
Carol Schuurmans
Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada
Frank Visser
Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
Shannon E. Dunn
Department of Immunology, Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, St. Michael’s Hospital, University of Toronto, Toronto, ON M5B 1W8, Canada
Shalina S. Ousman
Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Cell Biology & Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada; Corresponding author
Summary: The cysteine protease inhibitor Cystatin C (CST3) is highly expressed in the brains of multiple sclerosis (MS) patients and C57BL/6J mice with experimental autoimmune encephalomyelitis (EAE; a model of MS), but its roles in the diseases are unknown. Here, we show that CST3 plays a detrimental function in myelin oligodendrocyte glycoprotein 35-55 (MOG35-55)-induced EAE but only in female animals. Female Cst3 null mice display significantly lower clinical signs of disease compared to wild-type (WT) littermates. This difference is associated with reduced interleukin-6 production and lower expression of key proteins (CD80, CD86, major histocompatibility complex [MHC] II, LC3A/B) involved in antigen processing, presentation, and co-stimulation in antigen-presenting cells (APCs). In contrast, male WT and Cst3−/− mice and cells show no differences in EAE signs or APC function. Further, the sex-dependent effect of CST3 in EAE is sensitive to gonadal hormones. Altogether, we have shown that CST3 has a sex-dependent role in MOG35-55-induced EAE.
