{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T14:15:03Z","timestamp":1772892903635,"version":"3.50.1"},"reference-count":37,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T00:00:00Z","timestamp":1632700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K06608, 17K09046"],"award-info":[{"award-number":["21K06608, 17K09046"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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-\u03baB 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.<\/jats:p>","DOI":"10.3390\/cells10102550","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T10:39:20Z","timestamp":1632739160000},"page":"2550","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Caspase-Dependent HMGB1 Release from Macrophages Participates in Peripheral Neuropathy Caused by Bortezomib, a Proteasome-Inhibiting Chemotherapeutic Agent, in Mice"],"prefix":"10.3390","volume":"10","author":[{"given":"Maho","family":"Tsubota","sequence":"first","affiliation":[{"name":"Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takaya","family":"Miyazaki","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuya","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusuke","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yui","family":"Aokiba","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiori","family":"Tomita","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumiko","family":"Sekiguchi","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0380-494X","authenticated-orcid":false,"given":"Dengli","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahiro","family":"Nishibori","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3163-807X","authenticated-orcid":false,"given":"Atsufumi","family":"Kawabata","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Li, Y., Lustberg, M.B., and Hu, S. 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