Macrophage-derived HMGB1 as a Pain Mediator in the Early Stage of Acute Pancreatitis in Mice: Targeting RAGE and CXCL12/CXCR4 Axis

Yuhei Irie, Maho Tsubota, Hiroyasu Ishikura, Fumiko Sekiguchi, Yuka Terada, Toshifumi Tsujiuchi, Keyue Liu, Masahiro Nishibori, Atsufumi Kawabata

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Extracellular high mobility group box 1 (HMGB1) activates the receptor for advanced glycation end products (RAGE) or Toll-like receptor 4 (TLR4) and forms a heterocomplex with CXCL12 that strongly activates CXCR4, promoting inflammatory and pain signals. In the present study, we investigated the role of HMGB1 in pancreatic pain accompanying cerulein-induced acute pancreatitis in mice. Abdominal referred hyperalgesia accompanying acute pancreatitis occurred within 1 h after 6 hourly injections of cerulein. The anti-HMGB1 neutralizing antibody or recombinant human soluble thrombomodulin (rhsTM), known to inactivate HMGB1, abolished the cerulein-induced referred hyperalgesia, but not pancreatitis itself. Plasma or pancreatic HMGB1 levels did not change, but macrophage infiltration into the pancreas occurred 1 h after cerulein treatment. Minocycline, a macrophage/microglia inhibitor, ethyl pyruvate that inhibits HMGB1 release from macrophages, or liposomal clodronate that depletes macrophages prevented the referred hyperalgesia, but not pancreatitis. Antagonists of RAGE or CXCR4, but not TLR4, strongly suppressed the cerulein-induced referred hyperalgesia, but not pancreatitis. Upregulation of RAGE, CXCR4 and CXCL12, but not TLR4, were detected in the pancreas 1 h after cerulein treatment. Our data suggest that HMGB1 regionally secreted by macrophages mediates pancreatic pain by targeting RAGE and CXCL12/CXCR4 axis in the early stage of acute pancreatitis.

Original languageEnglish
Pages (from-to)1-15
Number of pages15
JournalJournal of NeuroImmune Pharmacology
DOIs
Publication statusAccepted/In press - Jul 28 2017

Fingerprint

Ceruletide
Pancreatitis
Macrophages
Hyperalgesia
Pain
Toll-Like Receptor 4
Pancreas
Clodronic Acid
Nociceptors
Minocycline
Microglia
Neutralizing Antibodies
Mouse Ager protein
Up-Regulation
Injections
Advanced Glycosylation End Product-Specific Receptor
Therapeutics

Keywords

  • CXCR4
  • HMGB1
  • Macrophage
  • Pancreatic pain
  • RAGE
  • Thrombomodulin

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

Cite this

Macrophage-derived HMGB1 as a Pain Mediator in the Early Stage of Acute Pancreatitis in Mice : Targeting RAGE and CXCL12/CXCR4 Axis. / Irie, Yuhei; Tsubota, Maho; Ishikura, Hiroyasu; Sekiguchi, Fumiko; Terada, Yuka; Tsujiuchi, Toshifumi; Liu, Keyue; Nishibori, Masahiro; Kawabata, Atsufumi.

In: Journal of NeuroImmune Pharmacology, 28.07.2017, p. 1-15.

Research output: Contribution to journalArticle

Irie, Yuhei ; Tsubota, Maho ; Ishikura, Hiroyasu ; Sekiguchi, Fumiko ; Terada, Yuka ; Tsujiuchi, Toshifumi ; Liu, Keyue ; Nishibori, Masahiro ; Kawabata, Atsufumi. / Macrophage-derived HMGB1 as a Pain Mediator in the Early Stage of Acute Pancreatitis in Mice : Targeting RAGE and CXCL12/CXCR4 Axis. In: Journal of NeuroImmune Pharmacology. 2017 ; pp. 1-15.
@article{4b2c91095975467691e403d8e47727b8,
title = "Macrophage-derived HMGB1 as a Pain Mediator in the Early Stage of Acute Pancreatitis in Mice: Targeting RAGE and CXCL12/CXCR4 Axis",
abstract = "Extracellular high mobility group box 1 (HMGB1) activates the receptor for advanced glycation end products (RAGE) or Toll-like receptor 4 (TLR4) and forms a heterocomplex with CXCL12 that strongly activates CXCR4, promoting inflammatory and pain signals. In the present study, we investigated the role of HMGB1 in pancreatic pain accompanying cerulein-induced acute pancreatitis in mice. Abdominal referred hyperalgesia accompanying acute pancreatitis occurred within 1 h after 6 hourly injections of cerulein. The anti-HMGB1 neutralizing antibody or recombinant human soluble thrombomodulin (rhsTM), known to inactivate HMGB1, abolished the cerulein-induced referred hyperalgesia, but not pancreatitis itself. Plasma or pancreatic HMGB1 levels did not change, but macrophage infiltration into the pancreas occurred 1 h after cerulein treatment. Minocycline, a macrophage/microglia inhibitor, ethyl pyruvate that inhibits HMGB1 release from macrophages, or liposomal clodronate that depletes macrophages prevented the referred hyperalgesia, but not pancreatitis. Antagonists of RAGE or CXCR4, but not TLR4, strongly suppressed the cerulein-induced referred hyperalgesia, but not pancreatitis. Upregulation of RAGE, CXCR4 and CXCL12, but not TLR4, were detected in the pancreas 1 h after cerulein treatment. Our data suggest that HMGB1 regionally secreted by macrophages mediates pancreatic pain by targeting RAGE and CXCL12/CXCR4 axis in the early stage of acute pancreatitis.",
keywords = "CXCR4, HMGB1, Macrophage, Pancreatic pain, RAGE, Thrombomodulin",
author = "Yuhei Irie and Maho Tsubota and Hiroyasu Ishikura and Fumiko Sekiguchi and Yuka Terada and Toshifumi Tsujiuchi and Keyue Liu and Masahiro Nishibori and Atsufumi Kawabata",
year = "2017",
month = "7",
day = "28",
doi = "10.1007/s11481-017-9757-2",
language = "English",
pages = "1--15",
journal = "Journal of NeuroImmune Pharmacology",
issn = "1557-1890",
publisher = "Springer New York",

}

TY - JOUR

T1 - Macrophage-derived HMGB1 as a Pain Mediator in the Early Stage of Acute Pancreatitis in Mice

T2 - Targeting RAGE and CXCL12/CXCR4 Axis

AU - Irie, Yuhei

AU - Tsubota, Maho

AU - Ishikura, Hiroyasu

AU - Sekiguchi, Fumiko

AU - Terada, Yuka

AU - Tsujiuchi, Toshifumi

AU - Liu, Keyue

AU - Nishibori, Masahiro

AU - Kawabata, Atsufumi

PY - 2017/7/28

Y1 - 2017/7/28

N2 - Extracellular high mobility group box 1 (HMGB1) activates the receptor for advanced glycation end products (RAGE) or Toll-like receptor 4 (TLR4) and forms a heterocomplex with CXCL12 that strongly activates CXCR4, promoting inflammatory and pain signals. In the present study, we investigated the role of HMGB1 in pancreatic pain accompanying cerulein-induced acute pancreatitis in mice. Abdominal referred hyperalgesia accompanying acute pancreatitis occurred within 1 h after 6 hourly injections of cerulein. The anti-HMGB1 neutralizing antibody or recombinant human soluble thrombomodulin (rhsTM), known to inactivate HMGB1, abolished the cerulein-induced referred hyperalgesia, but not pancreatitis itself. Plasma or pancreatic HMGB1 levels did not change, but macrophage infiltration into the pancreas occurred 1 h after cerulein treatment. Minocycline, a macrophage/microglia inhibitor, ethyl pyruvate that inhibits HMGB1 release from macrophages, or liposomal clodronate that depletes macrophages prevented the referred hyperalgesia, but not pancreatitis. Antagonists of RAGE or CXCR4, but not TLR4, strongly suppressed the cerulein-induced referred hyperalgesia, but not pancreatitis. Upregulation of RAGE, CXCR4 and CXCL12, but not TLR4, were detected in the pancreas 1 h after cerulein treatment. Our data suggest that HMGB1 regionally secreted by macrophages mediates pancreatic pain by targeting RAGE and CXCL12/CXCR4 axis in the early stage of acute pancreatitis.

AB - Extracellular high mobility group box 1 (HMGB1) activates the receptor for advanced glycation end products (RAGE) or Toll-like receptor 4 (TLR4) and forms a heterocomplex with CXCL12 that strongly activates CXCR4, promoting inflammatory and pain signals. In the present study, we investigated the role of HMGB1 in pancreatic pain accompanying cerulein-induced acute pancreatitis in mice. Abdominal referred hyperalgesia accompanying acute pancreatitis occurred within 1 h after 6 hourly injections of cerulein. The anti-HMGB1 neutralizing antibody or recombinant human soluble thrombomodulin (rhsTM), known to inactivate HMGB1, abolished the cerulein-induced referred hyperalgesia, but not pancreatitis itself. Plasma or pancreatic HMGB1 levels did not change, but macrophage infiltration into the pancreas occurred 1 h after cerulein treatment. Minocycline, a macrophage/microglia inhibitor, ethyl pyruvate that inhibits HMGB1 release from macrophages, or liposomal clodronate that depletes macrophages prevented the referred hyperalgesia, but not pancreatitis. Antagonists of RAGE or CXCR4, but not TLR4, strongly suppressed the cerulein-induced referred hyperalgesia, but not pancreatitis. Upregulation of RAGE, CXCR4 and CXCL12, but not TLR4, were detected in the pancreas 1 h after cerulein treatment. Our data suggest that HMGB1 regionally secreted by macrophages mediates pancreatic pain by targeting RAGE and CXCL12/CXCR4 axis in the early stage of acute pancreatitis.

KW - CXCR4

KW - HMGB1

KW - Macrophage

KW - Pancreatic pain

KW - RAGE

KW - Thrombomodulin

UR - http://www.scopus.com/inward/record.url?scp=85026464171&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85026464171&partnerID=8YFLogxK

U2 - 10.1007/s11481-017-9757-2

DO - 10.1007/s11481-017-9757-2

M3 - Article

C2 - 28755135

AN - SCOPUS:85026464171

SP - 1

EP - 15

JO - Journal of NeuroImmune Pharmacology

JF - Journal of NeuroImmune Pharmacology

SN - 1557-1890

ER -