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, Zhou Wu, Kenji Yamamoto, Jun Ichi Kira, Hiroshi Nakanishi, Yoshinori Hayashi

Research output: Contribution to journalArticle

1 Citation (Scopus)

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

Fingerprint

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; Wu, Zhou; 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 ; Wu, Zhou ; 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.
@article{ed54178b9d6d402397c8c956fc10a52d,
title = "Cathepsin E in neutrophils contributes to the generation of neuropathic pain in experimental autoimmune encephalomyelitis",
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.",
author = "Yuka Harada and Jing Zhang and Kazuhisa Imari and Ryo Yamasaki and Junjun Ni and Zhou Wu and Kenji Yamamoto and Kira, {Jun Ichi} and Hiroshi Nakanishi and Yoshinori Hayashi",
year = "2019",
month = "9",
day = "1",
doi = "10.1097/j.pain.0000000000001596",
language = "English",
volume = "160",
pages = "2050--2062",
journal = "Pain",
issn = "0304-3959",
publisher = "Elsevier",
number = "9",

}

TY - JOUR

T1 - Cathepsin E in neutrophils contributes to the generation of neuropathic pain in experimental autoimmune encephalomyelitis

AU - Harada, Yuka

AU - Zhang, Jing

AU - Imari, Kazuhisa

AU - Yamasaki, Ryo

AU - Ni, Junjun

AU - Wu, Zhou

AU - Yamamoto, Kenji

AU - Kira, Jun Ichi

AU - Nakanishi, Hiroshi

AU - Hayashi, Yoshinori

PY - 2019/9/1

Y1 - 2019/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85070816894&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070816894&partnerID=8YFLogxK

U2 - 10.1097/j.pain.0000000000001596

DO - 10.1097/j.pain.0000000000001596

M3 - Article

C2 - 31095099

AN - SCOPUS:85070816894

VL - 160

SP - 2050

EP - 2062

JO - Pain

JF - Pain

SN - 0304-3959

IS - 9

ER -