Pronociceptive Roles of Schwann Cell–Derived Galectin-3 in Taxane-Induced Peripheral Neuropathy

Abstract

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 line RAW 264.7. In addition, perineural administration of galectin-3 to the sciatic nerve of naive mice mimicked paclitaxel-induced 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. Significance: These findings demonstrate that the elevation of plasma galectin-3 is a CIPN-related pathologic change common to humans and mice, and that targeting galectin-3 is a therapeutic option to delay CIPN progression.

Acute postoperative pain and dorsal root ganglia transcriptomic signatures following total knee arthroplasty (TKA) in rats: An experimental study

“…Transcripts associated with inflammation, cytokine signaling, MAPK pathway, and transcription factors were enriched in our analysis. Utilizing established single-cell DRG RNA-seq datasets, it is likely that these transcripts originate from macrophages and Schwann cells, both of which release cytokines and chemokines and are implicated in the pathogenesis of pain [41][42][43]. This is consistent with previous work demonstrating that depletion of myeloid cells (including macrophages) alleviates postoperative pain hypersensitivity [43].…”

Neurotrophin-3 (NT-3) as a Potential Biomarker of the Peripheral Nervous System Damage Following Breast Cancer Treatment

“…However, the level of Gal-3 in studied patients constituted 5450.0 [4080.0; 9900.0] ng/mL and did not differ significantly from the group of healthy volunteers (4660.0 [3240.0; 6380.0] ng/mL) with p = 0.26. Based on the presented data from Koyanagi et al (2021), we expected to detect changes in galectin-3 in patients in the group with CPIN symptoms [ 52 ]. However, the level of gal-3 in this group was 5090.0 [4070.0; 8760.0] ng/mL and did not differ significantly from the level of this marker in patients without spinal symptoms (6340.0 [4620.0; 9900.0] ng/mL) and in healthy volunteers (4660.0 [3240.0; 6380.0] ng/mL).…”

“…It has also been demonstrated that inhibition of Gal-3 can suppress neuroinflammation, alleviate neuropathic pain caused by damage to peripheral nerves, and accelerate the recovery of nervous tissue [ 51 ]. Koyanagi et al hypothesized that Schwann cell galectin-3, released into the extracellular compartment, could be involved in the pathogenesis of CIPN by dedifferentiation and mitochondrial dysfunction, particularly following the chemotherapy with the taxane group agents [ 52 ].…”

Integrated Medicine for Chemotherapy-Induced Peripheral Neuropathy

“…Recently, the stimulator of interferon genes-interferon type I (STING-IFN-I) signaling axis was recognized as a critical regulator of physiological nociception and a promising target for treating CIPN [44]. Galactin-3 released by Schwann cells was also reported as a critical factor to cause CIPN [45].…”