Caspase-Dependent HMGB1 Release from Macrophages Participates in Peripheral Neuropathy Caused by Bortezomib, a Proteasome-Inhibiting Chemotherapeutic Agent, in Mice
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 m...
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MDPI AG
2021-09-01
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| author | Maho Tsubota Takaya Miyazaki Yuya Ikeda Yusuke Hayashi Yui Aokiba Shiori Tomita Fumiko Sekiguchi Dengli Wang Masahiro Nishibori Atsufumi Kawabata |
| author_facet | Maho Tsubota Takaya Miyazaki Yuya Ikeda Yusuke Hayashi Yui Aokiba Shiori Tomita Fumiko Sekiguchi Dengli Wang Masahiro Nishibori Atsufumi Kawabata |
| author_sort | Maho Tsubota |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T06:39:39Z |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-03-10T06:39:39Z |
| publishDate | 2021-09-01 |
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| series | Cells |
| spelling | doaj.art-9146743ea4a746819bc386eadfff587d2023-11-22T17:45:26ZengMDPI AGCells2073-44092021-09-011010255010.3390/cells10102550Caspase-Dependent HMGB1 Release from Macrophages Participates in Peripheral Neuropathy Caused by Bortezomib, a Proteasome-Inhibiting Chemotherapeutic Agent, in MiceMaho Tsubota0Takaya Miyazaki1Yuya Ikeda2Yusuke Hayashi3Yui Aokiba4Shiori Tomita5Fumiko Sekiguchi6Dengli Wang7Masahiro Nishibori8Atsufumi Kawabata9Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, JapanLaboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, JapanLaboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, JapanLaboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, JapanLaboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, JapanLaboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, JapanLaboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, JapanDepartment of Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, JapanDepartment of Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, JapanLaboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashiosaka 577-8502, JapanGiven 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.https://www.mdpi.com/2073-4409/10/10/2550bortezomibhigh mobility group box 1 (HMGB1)chemotherapy-induced peripheral neuropathymacrophagecaspaseapoptosis |
| spellingShingle | Maho Tsubota Takaya Miyazaki Yuya Ikeda Yusuke Hayashi Yui Aokiba Shiori Tomita Fumiko Sekiguchi Dengli Wang Masahiro Nishibori Atsufumi Kawabata Caspase-Dependent HMGB1 Release from Macrophages Participates in Peripheral Neuropathy Caused by Bortezomib, a Proteasome-Inhibiting Chemotherapeutic Agent, in Mice Cells bortezomib high mobility group box 1 (HMGB1) chemotherapy-induced peripheral neuropathy macrophage caspase apoptosis |
| title | Caspase-Dependent HMGB1 Release from Macrophages Participates in Peripheral Neuropathy Caused by Bortezomib, a Proteasome-Inhibiting Chemotherapeutic Agent, in Mice |
| title_full | Caspase-Dependent HMGB1 Release from Macrophages Participates in Peripheral Neuropathy Caused by Bortezomib, a Proteasome-Inhibiting Chemotherapeutic Agent, in Mice |
| title_fullStr | Caspase-Dependent HMGB1 Release from Macrophages Participates in Peripheral Neuropathy Caused by Bortezomib, a Proteasome-Inhibiting Chemotherapeutic Agent, in Mice |
| title_full_unstemmed | Caspase-Dependent HMGB1 Release from Macrophages Participates in Peripheral Neuropathy Caused by Bortezomib, a Proteasome-Inhibiting Chemotherapeutic Agent, in Mice |
| title_short | Caspase-Dependent HMGB1 Release from Macrophages Participates in Peripheral Neuropathy Caused by Bortezomib, a Proteasome-Inhibiting Chemotherapeutic Agent, in Mice |
| title_sort | caspase dependent hmgb1 release from macrophages participates in peripheral neuropathy caused by bortezomib a proteasome inhibiting chemotherapeutic agent in mice |
| topic | bortezomib high mobility group box 1 (HMGB1) chemotherapy-induced peripheral neuropathy macrophage caspase apoptosis |
| url | https://www.mdpi.com/2073-4409/10/10/2550 |
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