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Macrophage migration inhibitory factor is a potential therapeutic target for cisplatin induced peripheral neuropathy
Hya El-Baroudy1,2, Bhadrapriya Sivakumar1,2, Ximena Mejia Delgadillo1,2
1Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Background:
Cisplatin (CP) is a potent chemotherapy drug used for the management of several cancers. However, the use of CP is associated with painful peripheral neuropathy. Effective therapies are currently unavailable for CP-induced peripheral neuropathy (CisIPN). Given the known association between pro-inflammatory cytokines and CisIPN, we explored the role of the pro-inflammatory cytokine, the macrophage migration inhibitory factor (MIF), in CisIPN.
Methods:
CisIPN was induced in normal and breast cancer mouse models. Circulating MIF levels in CisIPN mice were examined using ELISA. The effect of MIF inhibition on CisIPN severity was evaluated using small molecule inhibitors. Mechanical and cold sensitivities of CisIPN mice were examined using Von Frey filament and cold acetone assays. Macrophage infiltration and expression of MIF in dorsal root ganglia (DRG) and sciatic nerves of CisIPN mice were examined using immunostaining. Molecular changes downstream of MIF were examined in Schwann Cells (SCs) using western blot.
Results:
Circulating MIF levels were increased in CisIPN mice, indicating a potential role for MIF in CisIPN. Pharmacological inhibition of MIF suppressed the mechanical hypersensitivity component associated with CisIPN, substantiating a facilitatory role for MIF in CisIPN. There was no significant change observed in macrophage abundance in DRGs and sciatic nerves of CisIPN mice. ELISA, immunostaining, and western blot assays indicated that sensory neurons and SCs are potential sources for increased MIF in CisIPN. We also found fluctuations in ERK1/2 signaling downstream of MIF in SCs, suggesting it as a potential mechanism underlying MIF-dependent facilitation of CisIPN.
Conclusions:
Overall, our results indicate that MIF facilitates CisIPN, suggesting its potential role as a therapeutic target for CisIPN.
