Pronociceptive roles of schwann cell-derived galectin-3 in taxane-induced peripheral neuropathy

Madoka Koyanagi, Satoshi Imai, Mayuna Matsumoto, Yoko Iguma, Nobuko Kawaguchi-Sakita, Takeshi Kotake, Yuki Iwamitsu, Mpumelelo Ntogwa, Ren Hiraiwa, Kazuki Nagayasu, Mamiko Saigo, Takashi Ogihara, Atsushi Yonezawa, Tomohiro Omura, Shunsaku Nakagawa, Takayuki Nakagawa, Kazuo Matsubara

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


Chemotherapy-induced peripheral neuropathy (CIPN) is a severe dose-limiting side effect of taxanes such as paclitaxel and docetaxel. Despite the high medical needs, insufficient understanding of the complex mechanism underlying CIPN pathogenesis precludes any endorsed causal therapy to prevent or relieve CIPN. In this study, we report that elevation of plasma galectin-3 level is a pathologic change common to both patients with taxane-treated breast cancer with CIPN and a mouse model of taxane-related CIPN. Following multiple intraperitoneal injections of paclitaxel in mice, galectin-3 levels were elevated in Schwann cells within the sciatic nerve but not in other peripheral organs or cells expressing galectin-3. Consistent with this, paclitaxel treatment of primary cultures of rat Schwann cells induced upregulation and secretion of galectin-3. In vitro migration assays revealed that recombinant galectin-3 induced a chemotactic response of the murine macrophage cell lineRAW264.7. In addition, perineural administration of galectin-3 to the sciatic nerve of naive mice mimicked paclitaxelinduced macrophage infiltration and mechanical hypersensitivity. By contrast, chemical depletion of macrophages by clodronate liposomes suppressed paclitaxel-induced mechanical hypersensitivity despite the higher level of plasma galectin-3. Deficiency (Galectin-3-/- mice) or pharmacologic inhibition of galectin-3 inhibited paclitaxel-induced macrophage infiltration and mechanical hypersensitivity. In conclusion, we propose that Schwann cell- derived galectin-3 plays a pronociceptive role via macrophage infiltration in the pathogenesis of taxane-induced peripheral neuropathy. Therapies targeting this phenomenon, which is common to patients with CIPN and mouse models, represent a novel approach to suppress taxane-related CIPN.

Original languageEnglish
Pages (from-to)2207-2219
Number of pages13
JournalCancer Research
Issue number8
Publication statusPublished - 2021 Apr
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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