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.
Taxanes frequently cause chemotherapy-induced peripheral neuropathy (CIPN). However, the mechanisms underlying CIPN pathogenesis are not fully understood. We previously showed that taxanes preferentially impair Schwann cells (SCs) by inducing dedifferentiation. In this study, we further examined the roles of dedifferentiated SCs in the development of CIPN. We found that mRNA expression of an inflammatory factor, X, was increased in dedifferentiated SC culture or the mouse sciatic nerve after paclitaxel (0.01 μM) treatment or repeated i.p. injection of paclitaxel (20 mg/kg), respectively. Furthermore, murine macrophage cell line (RAW264.7) showed a chemotaxis response toward the conditioned medium of paclitaxel-treated SCs. Consistent with this, we found that the perineural application of an inflammatory factor derived from dedifferentiated SCs induced infiltration of macrophages into the sciatic nerve and mechanical hypersensitivity in mice. Taken together, our findings allow us to conclude that, in response to paclitaxel treatment, an inflammatory factor is released from dedifferentiated SCs to chemoattract macrophages. These SC-dependent macrophage migration may participate in paclitaxel-induced CIPN pathogenesis.
BACKGROUND: Distal sensory neuropathy (DSN) is a hallmark of human immunodeficiency virus (HIV) infections, affecting as many as 50% of all individuals infected with HIV, and can result in persistent and disabling pain. Direct neurotoxicity through infection of neurons with HIV has been proposed to be associated with the pathogenesis of HIV DSN. However, it remains controversial whether HIV can enter neurons and thus be directly neurotoxic. Alternatively, a growing body of evidence suggests that the indirect neurotoxicity of HIV through inflammatory responses to viral envelope proteins, such as gp120, is an essential mechanism of HIV DSN pathogenesis. In this study, we examined the impact of gp120 on innate immune systems that could explain how the envelope protein induces DSN. METHODS: The HIV DSN model was generated by applying either HIV-gp120 (IIIB and MN strain) or its vehicle to the sciatic nerve of C57BL/6J mice (5-7 weeks old), using oxidized cellulose to deliver proteins directly to the sciatic nerve. Paw withdrawal thresholds to a tactile stimulus to the ipsilateral hindpaw was assessed at baseline and on post-surgical days 3, 7, 14, 21 and 28. Spontaneous pain-associated behaviors were assessed by visual observation of the operated limb on post-surgical day 7. Animals were sacrificed and perfused on day 7 to collect samples of the sciatic nerve, dorsal root ganglion and spinal cord for immunohistochemistry and flow cytometry examination. RESULTS: Application of gp120 IIIB or MN strain to the sciatic nerve significantly reduced paw withdrawal threshold to a tactile stimulus in the ipsilateral hind paw 7 days after treatment. Spontaneous pain-like behaviors were also significantly increased 7days after gp120 treatment. Flow cytometry and immunohistochemical studies revealed a marked increase in F4/80-and Iba1-positive macrophage within the ipsilateral sides of both gp120 treated sciatic nerves and DRG 7days after gp120 treatment. Peripheral macrophage deletion by clodronate liposomes completely abolished both gp120induced mechanical allodynia and spontaneous pain-like behaviors. CONCLUSIONS: Present findings suggest that macrophages play a key role in the HIV pathogenesis of evoked and spontaneous pain in HIV DSN. Further identification of key molecules released by macrophages which mediate HIV DSN is needed.
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