Caspase-dependent hmgb1 release from macrophages participates in peripheral neuropathy caused by bortezomib, a proteasome-inhibiting chemotherapeutic agent, in mice

Maho Tsubota, Takaya Miyazaki, Yuya Ikeda, Yusuke Hayashi, Yui Aokiba, Shiori Tomita, Fumiko Sekiguchi, Dengli Wang, Masahiro Nishibori, Atsufumi Kawabata

Research output: Contribution to journalArticlepeer-review

Abstract

Given the role of macrophage-derived high mobility group box 1 (HMGB1) in chemotherapy-induced peripheral neuropathy (CIPN) caused by paclitaxel, we analyzed the role of HMGB1 and macrophages in the CIPN caused by bortezomib, a proteasome-inhibiting chemotherapeutic agent used for the treatment of multiple myeloma. Repeated administration of bortezomib caused CIPN accompanied by early-stage macrophage accumulation in the dorsal root ganglion. This CIPN was prevented by an anti-HMGB1-neutralizing antibody, thrombomodulin alfa capable of accelerating thrombin-dependent degradation of HMGB1, antagonists of the receptor for advanced glycation end-products (RAGE) and C-X-C motif chemokine receptor 4 (CXCR4), known as HMGB1-targeted membrane receptors, or macrophage depletion with liposomal clodronate, as reported in a CIPN model caused by paclitaxel. In macrophage-like RAW264.7 cells, bortezomib as well as MG132, a well-known proteasome inhibitor, caused HMGB1 release, an effect inhibited by caspase inhibitors but not inhibitors of NF-κB and p38 MAP kinase, known to mediate paclitaxel-induced HMGB1 release from macrophages. Bortezomib increased cleaved products of caspase-8 and caused nuclear fragmentation or condensation in macrophages. Repeated treatment with the caspase inhibitor prevented CIPN caused by bortezomib in mice. Our findings suggest that bortezomib causes caspase-dependent release of HMGB1 from macrophages, leading to the development of CIPN via activation of RAGE and CXCR4.

Original languageEnglish
Article number2550
JournalCells
Volume10
Issue number10
DOIs
Publication statusPublished - Oct 2021

Keywords

  • Apoptosis
  • Bortezomib
  • Caspase
  • Chemotherapy-induced peripheral neuropathy
  • High mobility group box 1 (HMGB1)
  • Macrophage

ASJC Scopus subject areas

  • Medicine(all)

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