High mobility group box 1 (HMGB1): dual functions in the cochlear auditory neurons in response to stress?
High mobility group box 1 (HMGB1) is a DNA-binding protein that facilitates gene transcription and may act extracellularly as a late mediator of inflammation. The roles of HMGB1 in the pathogenesis of the spiral ganglion neurons (SGNs) of the cochlea are currently unknown. In the present study, we tested the hypothesis that early phenotypical changes in the SGNs of the amikacin-poisoned rat cochlea are mediated by HMGB1. Our results showed that a marked downregulation of HMGB1 had occurred by completion of amikacin treatment, coinciding with acute damage at the dendrite extremities of the SGNs. A few days later, during the recovery of the SGN dendrites, the protein was re-expressed and transiently accumulated within the nuclei of the SGNs. The phosphorylated form of the transcription factor c-Jun (p-c-Jun) was concomitantly detected in the nuclei of the SGNs where it often co-localized with HMGB1, while the anti-apoptotic protein BCL2 was over-expressed in the cytoplasm. In animals co-treated with amikacin and the histone deacetylase inhibitor trichostatin A, both HMGB1 and p-c-Jun were exclusively found within the cytoplasm. The initial disappearance of HMGB1 from the affected SGNs may be due to its release into the external medium, where it may have a cytokine-like function. Once re-expressed and translocated into the nucleus, HMGB1 may facilitate the transcriptional activity of p-c-Jun, which in turn may promote repair mechanisms. Our study therefore suggests that HMGB1 can positively influence the survival of SGNs following ototoxic exposure via both its extracellular and intranuclear functions.
KeywordsExcitotoxicity Ototoxicity c-Jun Gamma-H2ax BCL2 TSA
We acknowledge Julien Menardo and Romain Lalandes for their helpful advice during the course of the experiments. Thanks are due to Hassan Boukhaddaoui for assistance in fluorescent imagery (technological platform Montpellier Rio Imaging (MRI)), and to Chantal Cazevieille and Alicia Caballero for assistance in electron microscopy (technological platform Correlative Microscopy and Electron Tomography (COMET)) at the Institute of Neurosciences of Montpellier (INM). Cryosections were made in the Experimental Histology Network of Montpellier (RHEM) of the INM. Experimental animals were given attentive care by the animal facility team of INM. The French Ministère de la Recherche et des Nouvelles Technologies provided financial support for cell imagery. The manuscript has been revised for the English by an independent scientific language editing service (Angloscribe, 30420-Calvisson, France).
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