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.

• Authors: Yuhei Irie, Maho Tsubota, Hiroyasu Ishikura, Fumiko Sekiguchi, Yuka Terada, Toshifumi Tsujiuchi, Keyue Liu, Masahiro Nishibori, Atsufumi Kawabata
• Journal: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology (J Neuroimmune Pharmacol) Vol. 12 Issue 4 Pg. 693-707 (Dec 2017) ISSN: 1557-1904 [Electronic] United States
• PMID: 28755135 (Publication Type: Journal Article)

Chemical References

• Ager protein, mouse
• CXCR4 protein, mouse
• Chemokine CXCL12
• Cxcl12 protein, mouse
• HMGB1 Protein
• HMGB1 protein, mouse
• Receptor for Advanced Glycation End Products
• Receptors, CXCR4

Topics

• Animals
• Chemokine CXCL12 (metabolism)
• HMGB1 Protein (metabolism)
• Macrophages (metabolism)
• Male
• Mice
• Pain (etiology, metabolism)
• Pancreatitis (complications, metabolism)
• Receptor for Advanced Glycation End Products (metabolism)
• Receptors, CXCR4 (metabolism)
• Signal Transduction (physiology)