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

doi:10.1016/j.celrep.2020.108236

Cystatin C Plays a Sex-Dependent Detrimental Role in Experimental Autoimmune Encephalomyelitis

Cell Rep. 2020 Oct 6;33(1):108236. doi: 10.1016/j.celrep.2020.108236.

Authors

Vahid Hoghooghi¹, Alexandra L Palmer¹, Ariana Frederick², Yulan Jiang², Jessica E Merkens¹, Anjali Balakrishnan³, Trisha M Finlay¹, Anders Grubb⁴, Efrat Levy⁵, Paul Gordon⁶, Frank R Jirik⁷, Minh Dang Nguyen⁸, Carol Schuurmans³, Frank Visser⁹, Shannon E Dunn¹⁰, Shalina S Ousman¹¹

Affiliations

¹ Department of Neuroscience, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
² Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
³ Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada.
⁴ Department of Clinical Chemistry, Lund University Hospital, SE 221 85 Lund, Sweden.
⁵ 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.
⁶ Cumming School of Medicine Centre for Health Genomics and Informatics, University of Calgary, Calgary, AB T2N 4N1, Canada.
⁷ Department of Biochemistry & Molecular Biology, and Department of Medicine, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
⁸ 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.
⁹ Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
¹⁰ 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.
¹¹ 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. Electronic address: sousman@ucalgary.ca.

Abstract

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 (MOG_35-55)-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 MOG_35-55-induced EAE.

Keywords: CST3; Cystatin C; antigen-presenting cells; experimental allergic encephalomyelitis; experimental autoimmune encephalomyelitis; multiple sclerosis; sex effect; sex hormones.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cystatin C / metabolism*
Encephalomyelitis, Autoimmune, Experimental / immunology*
Female
Mice
Multiple Sclerosis / immunology*
Sex Factors

Substances

Cystatin C

Abstract

Publication types

MeSH terms

Substances

Grants and funding