Upregulation of TLR9 in the Dorsal Root Ganglia after Paclitaxel treatment


LEVIN Shahaf

Year of publication 2018
Type Appeared in Conference without Proceedings
Description Introduction The chemotherapeutic agent Paclitaxel is widely used in treatment of solid tumors. The major side effect of Paclitaxel treatment is peripheral neuropathy based on alteration of calcium channels and defragmentation of mitochondria in peripheral nerve axons. These changes are associated with the release of damage-associated molecular patterns (DAMPs) from the damaged axons. It is well known that DAMPs act on toll-like receptor 9 (TLR9) which plays a crucial role in innate immunity in humans. Activation of the TLR9 induces production of cytokines and chemokines that stimulates the inflammatory response. The aim of our study was to assess the changes in expression of the TLR9 in the dorsal root ganglia (DRGs) after Paclitaxel treatment. Material and methods The experiment was performed on 36 male Wistar rats. These animals underwent four intraperitoneal injections of either Paclitaxel (experimental group; n=20; cumulative dose of 8 mg/kg) or vehiculum (control group; n=12). Control and experimental animals were sacrificed after 1, 3, 7 and 14 days from the last application together with naive animals (n=4). Following a transcardial infusion with Zamboni´s fixative solution, lumbar DRGs were removed and cryostat longitudinal sections were performed. The sections were stained for TLR9, evaluated under a fluorescence microscope and the intensity was quantified by image analysis. Expression of TLR9 in the satellite glial cells (SGCs) was assessed under confocal microscopy using double immunostaining for glutamine synthetase. Results The presence of TLR9 was found in the cytoplasm of DRG neurons and SGCs. Statistically significant increase of TLR9 immunofluorescence was found in neurons of animals treated with Paclitaxel in comparison to the control and naive groups. Intensity of TLR9 immunofluorescence in neurons was increased with the time of survival after the last Paclitaxel injection. Statistically significant increased TLR9 immunostaining was found in neurons 14 days after the last Paclitaxel injection comparing to 1, 3 and 7 days. Intensity of TLR9 immunostaining in neurons was significantly increased in control animals comparing to naive animals. Conclusion Intraperitoneal treatment with Paclitaxel resulted in an upregulation of TLR9 in the DRG neurons comparing to control and naive animals. It is known that TLR9 is a receptor for DAMPs which are released into the blood after cellular damage. We suggest that these ligands can reach the DRGs via the blood circulation after Paclitaxel treatment.
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