Paclitaxel-induced HMGB1 release from macrophages and its implication for peripheral neuropathy in mice: Evidence for a neuroimmune crosstalk

Fumiko Sekiguchi, Risa Domoto, Kana Nakashima, Daichi Yamasoba, Hiroki Yamanishi, Maho Tsubota, Hidenori Wake, Masahiro Nishibori, Atsufumi Kawabata

Research output: Contribution to journalArticle

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Abstract

Given our recent evidence for the role of high mobility group box 1 (HMGB1) in chemotherapy-induced peripheral neuropathy (CIPN) in rats, we examined the origin of HMGB1 and the upstream and downstream mechanisms of HMGB1 release involved in paclitaxel-induced neuropathy in mice. Paclitaxel treatment developed mechanical allodynia in mice, as assessed by von Frey test, which was prevented by an anti-HMGB1-neutralizing antibody or thrombomodulin alfa capable of inactivating HMGB1. RAGE or CXCR4 antagonists, ethyl pyruvate or minocycline, known to inhibit HMGB1 release from macrophages, and liposomal clodronate, a macrophage depletor, prevented the paclitaxel-induced allodynia. Paclitaxel caused upregulation of RAGE and CXCR4 in the dorsal root ganglia and macrophage accumulation in the sciatic nerve. In macrophage-like RAW264.7 cells, paclitaxel evoked cytoplasmic translocation of nuclear HMGB1 followed by its extracellular release, and overexpression of CBP and PCAF, histone acetyltransferases (HATs), known to cause acetylation and cytoplasmic translocation of HMGB1, which were suppressed by ethyl pyruvate, N-acetyl-L-cysteine, an anti-oxidant, and SB203580 and PDTC, inhibitors of p38 MAP kinase (p38MAPK) and NF-κB, respectively. Paclitaxel increased accumulation of reactive oxygen species (ROS) and phosphorylation of p38MAPK, NF-κB p65 and I-κB in RAW264.7 cells. In mice, N-acetyl-L-cysteine or PDTC prevented the paclitaxel-induced allodynia. Co-culture of neuron-like NG108-15 cells or stimulation with their conditioned medium promoted paclitaxel-induced HMGB1 release from RAW264.7 cells. Our data indicate that HMGB1 released from macrophages through the ROS/p38MAPK/NF-κB/HAT pathway participates in the paclitaxel-induced peripheral neuropathy in mice, and unveils an emerging therapeutic avenue targeting a neuroimmune crosstalk in CIPN.

Original languageEnglish
Pages (from-to)201-213
Number of pages13
JournalNeuropharmacology
Volume141
DOIs
Publication statusPublished - Oct 1 2018

Fingerprint

Peripheral Nervous System Diseases
Paclitaxel
Macrophages
Hyperalgesia
p38 Mitogen-Activated Protein Kinases
Histone Acetyltransferases
Acetylcysteine
Reactive Oxygen Species
Clodronic Acid
Thrombomodulin
Drug Therapy
Minocycline
Spinal Ganglia
Sciatic Nerve
Acetylation
Conditioned Culture Medium
Coculture Techniques
Neutralizing Antibodies
Oxidants
Up-Regulation

Keywords

  • Chemotherapy-induced peripheral neuropathy
  • High mobility group box 1 (HMGB1)
  • Macrophage
  • Paclitaxel
  • Reactive oxygen species (ROS)

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

Paclitaxel-induced HMGB1 release from macrophages and its implication for peripheral neuropathy in mice : Evidence for a neuroimmune crosstalk. / Sekiguchi, Fumiko; Domoto, Risa; Nakashima, Kana; Yamasoba, Daichi; Yamanishi, Hiroki; Tsubota, Maho; Wake, Hidenori; Nishibori, Masahiro; Kawabata, Atsufumi.

In: Neuropharmacology, Vol. 141, 01.10.2018, p. 201-213.

Research output: Contribution to journalArticle

Sekiguchi, Fumiko ; Domoto, Risa ; Nakashima, Kana ; Yamasoba, Daichi ; Yamanishi, Hiroki ; Tsubota, Maho ; Wake, Hidenori ; Nishibori, Masahiro ; Kawabata, Atsufumi. / Paclitaxel-induced HMGB1 release from macrophages and its implication for peripheral neuropathy in mice : Evidence for a neuroimmune crosstalk. In: Neuropharmacology. 2018 ; Vol. 141. pp. 201-213.
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