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

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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.

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Acknowledgements

This work was supported by JSPS KAKENHI Grant Number 26460710, and also in part by the MEXT-Supported Program for the Strategic Research Foundation at Private Universities (2014-2018) (S1411037) and the “Antiaging” Project for Private Universities.

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  1. Yuhei Irie and Maho Tsubota contributed equally to this study.

Authors and Affiliations

  1. Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formally known as Kinki University), 3-4-1 Kowakae, Higashi-Osaka, 577-8502, Japan

    Yuhei Irie, Maho Tsubota, Fumiko Sekiguchi, Yuka Terada & Atsufumi Kawabata

  2. Division of Emergency and Critical Care Medicine, Fukuoka University, Hospital, Fukuoka, 814-0180, Japan

    Yuhei Irie & Hiroyasu Ishikura

  3. Department of Life Science, Faculty of Science and Engineering, Kindai University (formally known as Kinki University), 3-4-1 Kowakae, Higashi-Osaka, 577-8502, Japan

    Toshifumi Tsujiuchi

  4. Department of Pharmacology, Okayama University Graduate School of Medicine, Okayama, 700-8558, Japan

    Keyue Liu & Masahiro Nishibori

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  1. Yuhei Irie
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  2. Maho Tsubota
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Correspondence to Atsufumi Kawabata.

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A. Kawabata has received research grants from Asahi Kasei Pharma Corporation.

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Irie, Y., Tsubota, M., Ishikura, H. et al. Macrophage-derived HMGB1 as a Pain Mediator in the Early Stage of Acute Pancreatitis in Mice: Targeting RAGE and CXCL12/CXCR4 Axis. J Neuroimmune Pharmacol 12, 693–707 (2017). https://doi.org/10.1007/s11481-017-9757-2

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