Caspase-Dependent HMGB1 Release from Macrophages Participates in Peripheral Neuropathy Caused by Bortezomib, a Proteasome-Inhibiting Chemotherapeutic Agent, in Mice.

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.

• Authors: Maho Tsubota, Takaya Miyazaki, Yuya Ikeda, Yusuke Hayashi, Yui Aokiba, Shiori Tomita, Fumiko Sekiguchi, Dengli Wang, Masahiro Nishibori, Atsufumi Kawabata
• Journal: Cells (Cells) Vol. 10 Issue 10 (09 27 2021) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 34685531 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• HMGB1 Protein
• HMGB1 protein, human
• Bortezomib

Topics

• Animals
• Antineoplastic Agents (adverse effects)
• Apoptosis
• Bortezomib (adverse effects)
• Disease Models, Animal
• HMGB1 Protein (metabolism)
• Male
• Mice
• Peripheral Nervous System Diseases (chemically induced)