Ryo Okada1,2, Xinwen Zhang3, Yuka Harada1, Zhou Wu1, Hiroshi Nakanishi4,5. 1. Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka, 812-8582, Japan. 2. Department of Chemistry, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan. 3. Center of Implant Dentistry, School of Somatology, China Medical University, Shenyang, 110122, China. 4. Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka, 812-8582, Japan. nakan@dent.kyushu-u.ac.jp. 5. Department of Pharmacology, Faculty of Pharmaceutical Sciences, Yasuda Women's University, Hiroshima, 731-0153, Japan. nakan@dent.kyushu-u.ac.jp.
Abstract
OBJECTIVE: The objective of this study is to investigate the role of cathepsin H (CatH), a lysosomal cysteine protease, in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. METHODS: EAE was induced in CatH-deficient mice (CatH-/-) and wild-type littermates (+/+) using myelin oligodendrocyte glycoprotein (MOG) 35-55. The effects of CatH deficiency were determined by clinical scoring, mRNA expression levels of Tbx21, Rorc and FoxP3, protein levels of poly(I:C)-induced toll-like receptor 3 (TLR3) and phosphorylation of IRF3, and secretion of interferon-β (IFN-β) by splenocytes. RESULTS AND CONCLUSIONS: CatH-/- showed a significantly earlier disease onset of EAE and increased Th1 cell differentiation in splenocytes. Splenocytes prepared from immunized CatH-/- showed a significant decrease in poly(I:C)-induced increased TLR3 expression, interferon regulatory factor 3 (IRF3) phospholylation and IFN-β secretion. Therefore, CatH deficiency impaired TLR3-mediated activation of IRF3 and consequent secretion of IFN-β from dendritic cells, leading to the enhancement of Th1 cell differentiation and consequent early disease onset of EAE.
OBJECTIVE: The objective of this study is to investigate the role of cathepsin H (CatH), a lysosomal cysteine protease, in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. METHODS: EAE was induced in CatH-deficientmice (CatH-/-) and wild-type littermates (+/+) using myelin oligodendrocyte glycoprotein (MOG) 35-55. The effects of CatH deficiency were determined by clinical scoring, mRNA expression levels of Tbx21, Rorc and FoxP3, protein levels of poly(I:C)-induced toll-like receptor 3 (TLR3) and phosphorylation of IRF3, and secretion of interferon-β (IFN-β) by splenocytes. RESULTS AND CONCLUSIONS:CatH-/- showed a significantly earlier disease onset of EAE and increased Th1 cell differentiation in splenocytes. Splenocytes prepared from immunized CatH-/- showed a significant decrease in poly(I:C)-induced increased TLR3 expression, interferon regulatory factor 3 (IRF3) phospholylation and IFN-β secretion. Therefore, CatH deficiency impaired TLR3-mediated activation of IRF3 and consequent secretion of IFN-β from dendritic cells, leading to the enhancement of Th1 cell differentiation and consequent early disease onset of EAE.
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