Cathepsin E in neutrophils contributes to the generation of neuropathic pain in experimental autoimmune encephalomyelitis

Yuka Harada, Jing Zhang, Kazuhisa Imari, Ryo Yamasaki, Junjun Ni, Hiro Take, Kenji Yamamoto, Jun-Ichi Kira, Hiroshi Nakanishi, Yoshinori Hayashi

Research output: Contribution to journalArticle

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Abstract

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 (CatE) mice were highly resistant to myelin oligodendrocyte glycoprotein (MOG35-55)-induced mechanical allodynia. After MOG35-55 immunization, neutrophils immediately accumulated in the dorsal root ganglion (DRG). Adoptive transfer of MOG35-55-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 MOG35-55-stimulated CatE neutrophils were transferred into the recipient C57BL/6 mice. MOG35-55 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 MOG35-55-stimulated neutrophils. MOG35-55 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.

Original languageEnglish
Pages (from-to)2050-2062
Number of pages13
JournalPain
Volume160
Issue number9
DOIs
Publication statusPublished - Sep 1 2019

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Cathepsin E
Autoimmune Experimental Encephalomyelitis
Neuralgia
Neutrophils
Hyperalgesia
Multiple Sclerosis
Spinal Ganglia
Inbred C57BL Mouse
Pain
Secretory Proteinase Inhibitory Proteins
Myelin-Oligodendrocyte Glycoprotein
Leukocyte Elastase
Toll-Like Receptor 4
Pain Threshold
Adoptive Transfer
Pancreatic Elastase
Immunization
Animal Models

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

Cite this

Cathepsin E in neutrophils contributes to the generation of neuropathic pain in experimental autoimmune encephalomyelitis. / Harada, Yuka; Zhang, Jing; Imari, Kazuhisa; Yamasaki, Ryo; Ni, Junjun; Take, Hiro; Yamamoto, Kenji; Kira, Jun-Ichi; Nakanishi, Hiroshi; Hayashi, Yoshinori.

In: Pain, Vol. 160, No. 9, 01.09.2019, p. 2050-2062.

Research output: Contribution to journalArticle

Harada, Yuka ; Zhang, Jing ; Imari, Kazuhisa ; Yamasaki, Ryo ; Ni, Junjun ; Take, Hiro ; Yamamoto, Kenji ; Kira, Jun-Ichi ; Nakanishi, Hiroshi ; Hayashi, Yoshinori. / Cathepsin E in neutrophils contributes to the generation of neuropathic pain in experimental autoimmune encephalomyelitis. In: Pain. 2019 ; Vol. 160, No. 9. pp. 2050-2062.
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