Cathepsin E in neutrophils contributes to the generation of neuropathic pain in experimental autoimmune encephalomyelitis
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- Yuka Harada
- Department of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University, Fukuoka, Japan,. Dr. Hayashi is now with the Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan
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- Jing Zhang
- Department of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University, Fukuoka, Japan,. Dr. Hayashi is now with the Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan
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- Kazuhisa Imari
- Department of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University, Fukuoka, Japan,. Dr. Hayashi is now with the Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan
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- Ryo Yamasaki
- Departments of Neurology and Neurological Therapeutics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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- Junjun Ni
- Department of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University, Fukuoka, Japan,. Dr. Hayashi is now with the Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan
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- Zhou Wu
- Department of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University, Fukuoka, Japan,. Dr. Hayashi is now with the Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan
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- Kenji Yamamoto
- Proteolysis Research Laboratory, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
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- Jun-ichi Kira
- Departments of Neurology and Neurological Therapeutics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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- Hiroshi Nakanishi
- Department of Pharmacology, Faculty of Pharmacy, Yasuda Women's University, Hiroshima, Japan
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- Yoshinori Hayashi
- Department of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University, Fukuoka, Japan,. Dr. Hayashi is now with the Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan
Description
<jats:title>Abstract</jats:title> <jats:p>Pain is a frequent and disabling symptom in patients with multiple sclerosis (MS); however, the underlying mechanisms of MS-related pain are not fully understood. Here, we demonstrated that cathepsin E (CatE) in neutrophils contributes to the generation of mechanical allodynia in experimental autoimmune encephalomyelitis, an animal model of MS. We showed that CatE-deficient (<jats:italic toggle="yes">CatE</jats:italic> <jats:sup> −/− </jats:sup>) mice were highly resistant to myelin oligodendrocyte glycoprotein (MOG<jats:sub>35-55</jats:sub>)-induced mechanical allodynia. After MOG<jats:sub>35-55</jats:sub> immunization, neutrophils immediately accumulated in the dorsal root ganglion (DRG). Adoptive transfer of MOG<jats:sub>35-55</jats:sub>-stimulated wild-type neutrophils into the dorsal root ganglion induced mechanical allodynia in the recipient C57BL/6 mice. However, the pain threshold did not change when MOG<jats:sub>35-55</jats:sub>-stimulated <jats:italic toggle="yes">CatE</jats:italic> <jats:sup> −/− </jats:sup> neutrophils were transferred into the recipient C57BL/6 mice. MOG<jats:sub>35-55</jats:sub> stimulation caused CatE-dependent secretion of elastase in neutrophils. Behavioral analyses revealed that sivelestat, a selective neutrophil elastase inhibitor, suppressed mechanical allodynia induced by adoptively transferred MOG<jats:sub>35-55</jats:sub>-stimulated neutrophils. MOG<jats:sub>35-55</jats:sub> directly bound to toll-like receptor 4, which led to increased production of CatE in neutrophils. Our findings suggest that inhibition of CatE-dependent elastase production in neutrophil might be a potential therapeutic target for pain in patients with MS.</jats:p>
Journal
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- Pain
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Pain 160 (9), 2050-2062, 2019-04-30
Ovid Technologies (Wolters Kluwer Health)