Cathepsin C modulates myelin oligodendrocyte glycoprotein‐induced experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is an autoimmune disease characterized by immune‐mediated inflammation, which attacks the myelin sheath. MS pursues a relapsing and remitting course with varying intervals between symptoms. The main clinical pathological features include inflammation, myelin sheath destructio...

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Published in:Journal of neurochemistry 2019-02, Vol.148 (3), p.413-425
Main Authors: Durose, Wilaiwan Wisessmith, Shimizu, Takahiro, Li, JiaYi, Abe, Manabu, Sakimura, Kenji, Chetsawang, Banthit, Tanaka, Kenji F., Suzumura, Akio, Tohyama, Koujiro, Ikenaka, Kazuhiro
Format: Article
Language:English
Subjects:
Animal models
Autoimmune diseases
cathepsin C
Central nervous system
cystatin F
Cystatins
Demyelinating diseases
Demyelination
Dipeptidyl-peptidase I
Experimental allergic encephalomyelitis
experimental autoimmune encephalomyelitis (EAE)
Glycoproteins
Lesions
Mice
Microglia
Multiple sclerosis
Myelin
Myelination
Oligodendrocyte-myelin glycoprotein
Plaques
Proteinase inhibitors
Shadows
Sheaths
Spinal cord
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Summary:Multiple sclerosis (MS) is an autoimmune disease characterized by immune‐mediated inflammation, which attacks the myelin sheath. MS pursues a relapsing and remitting course with varying intervals between symptoms. The main clinical pathological features include inflammation, myelin sheath destruction and plaque formation in the central nervous system (CNS). We previously reported that cystatin F (CysF) expression is induced in demyelinating lesions that are accompanied by active remyelination (referred to as shadow plaques) but is down‐regulated in chronic demyelinated lesions (plaques) in the spinal cord of MS patients and in several murine models of demyelinating disease. CysF is a cathepsin protease inhibitor whose major target is cathepsin C (CatC), which is co‐expressed in demyelinating regions in Plp4e/− mice, a model of chronic demyelination. Here, we report the time course of CatC and CysF expression and describe the symptoms in a mouse experimental autoimmune encephalomyelitis (EAE) model using CatC knockdown (KD) and CatC over‐expression (OE) mice. In myelin oligodendrocyte glycoprotein (MOG)‐EAE, CatC positive cells were found to infiltrate the CNS at an early stage prior to any clinical signs, in comparison to WT mice. CysF expression was not observed at this early stage, but appeared later within shadow plaques. CatC expression was found in chronic demyelinated lesions but was not associated with CysF expression, and CatCKD EAE mouse showed delayed demyelination. Whereas, CatCOE in microglia significantly increased severity of demyelination in the MOG‐EAE model. Thus, these results demonstrate that CatC plays a major role in MOG‐EAE. Cathepsin C (CatC) plays a major role in autoimmune induced demyelination, MOG‐EAE model: CatC is expressed in microglia and neutrophil at an early demyelination. Modulation of CatC level in microglia affected in severity of demyelination. CatC and Cystatin F (CysF) interaction play an important role in both pathogenesis and progress of inflammatory demyelination. The finding in this study might be important for developing new therapeutic approaches to demyelinating diseases.
ISSN:0022-3042
1471-4159
DOI:10.1111/jnc.14581