Skip to main content

Advertisement

SpringerLink
Log in

Role of Thrombin in Soluble Thrombomodulin-Induced Suppression of Peripheral HMGB1-Mediated Allodynia in Mice

  • ORIGINAL ARTICLE
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

High mobility group box 1 (HMGB1), a nuclear protein, once released into the extracellular space under pathological conditions, plays a pronociceptive role in redox-dependent distinct active forms, all-thiol HMGB1 (at-HMGB1) and disulfide HMGB1 (ds-HMGB1), that accelerate nociception through the receptor for advanced glycation endproducts (RAGE) and Toll-like receptor 4 (TLR4), respectively. Thrombomodulin (TM), an endothelial membrane protein, and soluble TM, known as TMα, promote thrombin-mediated activation of protein C and also sequester HMGB1, which might facilitate thrombin degradation of HMGB1. The present study aimed at clarifying the role of thrombin in TMα-induced suppression of peripheral HMGB1-dependent allodynia in mice. Thrombin-induced degradation of at-HMGB1 and ds-HMGB1 was accelerated by TMα in vitro. Intraplantar (i.pl.) injection of bovine thymus-derived HMGB1 in an unknown redox state, at-HMGB1, ds-HMGB1 or lipopolysaccharide (LPS), known to cause HMGB1 secretion, produced long-lasting mechanical allodynia in mice, as assessed by von Frey test. TMα, when preadministered i.pl., prevented the allodynia caused by bovine thymus-derived HMGB1, at-HMGB1, ds-HMGB1 or LPS, in a dose-dependent manner. The TMα-induced suppression of the allodynia following i.pl. at-HMGB1, ds-HMGB1 or LPS was abolished by systemic preadministration of argatroban, a thrombin-inhibiting agent, and accelerated by i.pl. co-administered thrombin. Our data clearly indicate that TMα is capable of promoting the thrombin-induced degradation of both at-HMGB1 and ds-HMGB1, and suppresses the allodynia caused by either HMGB1 in a thrombin-dependent manner. Considering the emerging role of HMGB1 in distinct pathological pain models, the present study suggests the therapeutic usefulness of TMα for treatment of intractable and/or persistent pain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Abeyama K, Stern DM, Ito Y, Kawahara K, Yoshimoto Y, Tanaka M, Uchimura T, Ida N, Yamazaki Y, Yamada S, Yamamoto Y, Yamamoto H, Iino S, Taniguchi N, Maruyama I (2005) The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest 115:1267–1274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Agalave NM, Svensson CI (2015) Extracellular high-mobility group box 1 protein (HMGB1) as a mediator of persistent pain. Mol Med 20:569–578

    PubMed  PubMed Central  Google Scholar 

  • Agalave NM, Larsson M, Abdelmoaty S, Su J, Baharpoor A, Lundback P, Palmblad K, Andersson U, Harris H, Svensson CI (2014) Spinal HMGB1 induces TLR4-mediated long-lasting hypersensitivity and glial activation and regulates pain-like behavior in experimental arthritis. Pain 155:1802–1813

    Article  CAS  PubMed  Google Scholar 

  • Asfaha S, Brussee V, Chapman K, Zochodne DW, Vergnolle N (2002) Proteinase-activated receptor-1 agonists attenuate nociception in response to noxious stimuli. Br J Pharmacol 135:1101–1106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cecchinato V, D'Agostino G, Raeli L, Uguccioni M (2016) Chemokine interaction with synergy-inducing molecules: fine tuning modulation of cell trafficking. J Leukoc Biol 99:851–855

    Article  CAS  PubMed  Google Scholar 

  • Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53:55–63

    Article  CAS  PubMed  Google Scholar 

  • Cheng TL, Lai CH, Shieh SJ, Jou YB, Yeh JL, Yang AL, Wang YH, Wang CZ, Chen CH, Shi GY, Ho ML, Wu HL (2016) Myeloid thrombomodulin lectin-like domain inhibits osteoclastogenesis and inflammatory bone loss. Sci Rep 6:28340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Conway EM (2012) Thrombomodulin and its role in inflammation. Semin Immunopathol 34:107–125

    Article  CAS  PubMed  Google Scholar 

  • Das N, Dewan V, Grace PM, Gunn RJ, Tamura R, Tzarum N, Watkins LR, Wilson IA, Yin H (2016) HMGB1 activates proinflammatory signaling via TLR5 leading to allodynia. Cell Rep 17:1128–1140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feldman P, Due MR, Ripsch MS, Khanna R, White FA (2012) The persistent release of HMGB1 contributes to tactile hyperalgesia in a rodent model of neuropathic pain. J Neuroinflammation 9:180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frank MG, Weber MD, Watkins LR, Maier SF (2015) Stress sounds the alarmin: the role of the danger-associated molecular pattern HMGB1 in stress-induced neuroinflammatory priming. Brain Behav Immun 48:1–7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Irie Y, Tsubota M, Ishikura H, Sekiguchi F, Terada Y, Tsujiuchi T, Liu K, Nishibori M, Kawabata A (2017) 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

  • Ito T, Maruyama I (2011) Thrombomodulin: protectorate God of the vasculature in thrombosis and inflammation. J Thromb Haemost 9(Suppl 1):168–173

    Article  CAS  PubMed  Google Scholar 

  • Ito T, Kawahara K, Okamoto K, Yamada S, Yasuda M, Imaizumi H, Nawa Y, Meng X, Shrestha B, Hashiguchi T, Maruyama I (2008) Proteolytic cleavage of high mobility group box 1 protein by thrombin-thrombomodulin complexes. Arterioscler Thromb Vasc Biol 28:1825–1830

    Article  CAS  PubMed  Google Scholar 

  • Kadono K, Uchida Y, Hirao H, Miyauchi T, Watanabe T, Iida T, Ueda S, Kanazawa A, Mori A, Okajima H, Terajima H, Uemoto S (2017) Thrombomodulin attenuates inflammatory damage due to liver ischemia and reperfusion injury in mice in toll-like receptor 4-dependent manner. Am J Transplant 17:69–80

    Article  CAS  PubMed  Google Scholar 

  • Kang R, Chen R, Zhang Q, Hou W, Wu S, Cao L, Huang J, Yu Y, Fan XG, Yan Z, Sun X, Wang H, Wang Q, Tsung A, Billiar TR, Zeh HJ 3rd, Lotze MT, Tang D (2014) HMGB1 in Health and Disease. J Molecular Aspects Medicine 40:111–116

  • Kato J, Svensson CI (2015) Role of extracellular damage-associated molecular pattern molecules (DAMPs) as mediators of persistent pain. Prog Mol Biol Transl Sci 131:251–279

    Article  PubMed  Google Scholar 

  • Kawabata A, Kawao N, Kuroda R, Tanaka A, Shimada C (2002) The PAR-1-activating peptide attenuates carrageenan-induced hyperalgesia in rats. Peptides 23:1181–1183

    Article  CAS  PubMed  Google Scholar 

  • Lin WL, Chang CF, Shi CS, Shi GY, Wu HL (2013) Recombinant lectin-like domain of thrombomodulin suppresses vascular inflammation by reducing leukocyte recruitment via interacting with Lewis Y on endothelial cells. Arterioscler Thromb Vasc Biol 33:2366–2373

    Article  CAS  PubMed  Google Scholar 

  • Maeda T, Ozaki M, Kobayashi Y, Kiguchi N, Kishioka S (2013) HMGB1 as a potential therapeutic target for neuropathic pain. J Pharmacol Sci 123:301–305

    Article  CAS  PubMed  Google Scholar 

  • Nakamura Y, Morioka N, Abe H, Zhang FF, Hisaoka-Nakashima K, Liu K, Nishibori M, Nakata Y (2013) Neuropathic pain in rats with a partial sciatic nerve ligation is alleviated by intravenous injection of monoclonal antibody to high mobility group box-1. PLoS One 8:e73640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishida T, Tsubota M, Kawaishi Y, Yamanishi H, Kamitani N, Sekiguchi F, Ishikura H, Liu K, Nishibori M, Kawabata A (2016) Involvement of high mobility group box 1 in the development and maintenance of chemotherapy-induced peripheral neuropathy in rats. Toxicology 365:48–58

    Article  CAS  PubMed  Google Scholar 

  • Shibasaki M, Sasaki M, Miura M, Mizukoshi K, Ueno H, Hashimoto S, Tanaka Y, Amaya F (2010) Induction of high mobility group box-1 in dorsal root ganglion contributes to pain hypersensitivity after peripheral nerve injury. Pain 149:514–521

    Article  CAS  PubMed  Google Scholar 

  • Tanaka J, Seki Y, Ishikura H, Tsubota M, Sekiguchi F, Yamaguchi K, Murai A, Umemura T, Kawabata A (2013) Recombinant human soluble thrombomodulin prevents peripheral HMGB1-dependent hyperalgesia in rats. Br J Pharmacol 170:1233–1241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tanaka J, Yamaguchi K, Ishikura H, Tsubota M, Sekiguchi F, Seki Y, Tsujiuchi T, Murai A, Umemura T, Kawabata A (2014) Bladder pain relief by HMGB1 neutralization and soluble thrombomodulin in mice with cyclophosphamide-induced cystitis. Neuropharmacology 79:112–118

    Article  CAS  PubMed  Google Scholar 

  • Venereau E, Casalgrandi M, Schiraldi M, Antoine DJ, Cattaneo A, De Marchis F, Liu J, Antonelli A, Preti A, Raeli L, Shams SS, Yang H, Varani L, Andersson U, Tracey KJ, Bachi A, Uguccioni M, Bianchi ME (2012) Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J Exp Med 209:1519–1528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Venereau E, De Leo F, Mezzapelle R, Careccia G, Musco G, Bianchi ME (2016) HMGB1 as biomarker and drug target. Pharmacol Res 111:534–544

    Article  CAS  PubMed  Google Scholar 

  • Wan W, Cao L, Khanabdali R, Kalionis B, Tai X, Xia S (2016) The emerging role of HMGB1 in neuropathic pain: a potential therapeutic target for neuroinflammation. J Immunol Res 2016:6430423

    Article  PubMed  PubMed Central  Google Scholar 

  • Yamasoba D, Tsubota M, Domoto R, Sekiguchi F, Nishikawa H, Liu K, Nishibori M, Ishikura H, Yamamoto T, Taga A, Kawabata A (2016) Peripheral HMGB1-induced hyperalgesia in mice: redox state-dependent distinct roles of RAGE and TLR4. J Pharmacol Sci 130:139–142

    Article  CAS  PubMed  Google Scholar 

  • Yang L, Rezaie AR (2003) The fourth epidermal growth factor-like domain of thrombomodulin interacts with the basic exosite of protein C. J Biol Chem 278:10484–10490

    Article  CAS  PubMed  Google Scholar 

Download references

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).

Author information

Author notes

  1. Ryuichi Tsujita, Maho Tsubota and Yusuke Hayashi 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

    Ryuichi Tsujita, Maho Tsubota, Yusuke Hayashi, Haruka Saeki, Fumiko Sekiguchi & Atsufumi Kawabata

  2. Project Management Development, Asahi Kasei Pharma Corporation, 1-105 Kanda Jinbocho, Chiyoda-ku, Tokyo, 101-8101, Japan

    Ryuichi Tsujita

Authors
  1. Ryuichi Tsujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maho Tsubota
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yusuke Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haruka Saeki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fumiko Sekiguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Atsufumi Kawabata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Atsufumi Kawabata.

Ethics declarations

Conflicts of Interest

R. Tsujita is an employee of Asahi Kasei Pharma Corporation, and A. Kawabata has received research grants from Asahi Kasei Pharma Corporation.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tsujita, R., Tsubota, M., Hayashi, Y. et al. Role of Thrombin in Soluble Thrombomodulin-Induced Suppression of Peripheral HMGB1-Mediated Allodynia in Mice. J Neuroimmune Pharmacol 13, 179–188 (2018). https://doi.org/10.1007/s11481-017-9773-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-017-9773-2

Keywords

Search

Navigation