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.

Immunogenic cell death after combined treatment with radiation and ATR inhibitors is dually regulated by apoptotic caspases

“…Notably our finding of caspase-dependent HMGB1 release is consistent with results in e.g. apoptosis-mediated sepsis (42) and for macrophages treated with a proteasome inhibitor (43). Furthermore, our results suggest that caspase inhibition does not always abolish the HMGB1 release, as shown for H1975 cells where the caspase inhibition also caused phosphorylation of MLKL, a necroptosis marker.…”

Peripheral Neuropathy During Concomitant Administration of Proteasome Inhibitors and Factor Xa Inhibitors: Identifying the Likelihood of Drug-Drug Interactions

“…A recent placebo-controlled, double-blind, randomized study indicates that recombinant thrombomodulin, which directly binds to HMGB1 and improves its degradation by thrombin, has a preventive effect against oxaliplatin-induced PN (Kotaka et al, 2020). Two preclinical studies also found that recombinant thrombomodulin could prevent peripheral neuropathy induced by bortezomib and paclitaxel in rats and mice (Miyamoto et al, 2021;Tsubota et al, 2021). Tsubota et al indicated that anticoagulant (argatroban) could promote bortezomib-induced peripheral neuropathy (BIPN) and cancel the anti-BIPN effect of recombinant thrombomodulin (Tsubota et al, 2021).…”

“…Two preclinical studies also found that recombinant thrombomodulin could prevent peripheral neuropathy induced by bortezomib and paclitaxel in rats and mice (Miyamoto et al, 2021;Tsubota et al, 2021). Tsubota et al indicated that anticoagulant (argatroban) could promote bortezomib-induced peripheral neuropathy (BIPN) and cancel the anti-BIPN effect of recombinant thrombomodulin (Tsubota et al, 2021). The impact of anticoagulants on PN was dose dependent.…”

“…A study found that three repeated oral administrations instead of a single administration of rivaroxaban reversed the anti-PN effect of thrombomodulin in animals treated with oxaliplatin ( Tsubota et al, 2019 ). Thrombomodulin at 3 mg/kg could prevent and reverse BIPN in mice rather than at the 1 mg/kg dose ( Tsubota et al, 2021 ).…”

Multiple functions of HMGB1 in cancer

“…In severe cases, dosage reduction or discontinuation of chemotherapy may be necessary. In recent years, numerous studies have investigated the pharmacological effects of HMGB1 on tumor pain and neuralgia, given its strong pro-inflammatory and propain activities ( 82 – 84 ). Studies have shown that an anti-HMGB1-neutralizing antibody can effectively inhibit CIPN in animals receiving chemotherapy ( 85 ).…”