JAK2/STAT3 inhibition attenuates noise-induced hearing loss.

Teresa Wilson,Irina Omelchenko,Alfred L Nuttall,Sarah Foster,Xiaorui Shi,Yuan Zhang,Berta Alsina

doi:10.1371/journal.pone.0108276

Abstract

Signal transducers and activators of transcription 3 (STAT3) is a stress responsive transcription factor that plays a key role in oxidative stress-mediated tissue injury. As reactive oxygen species (ROS) are a known source of damage to tissues of the inner ear following loud sound exposure, we examined the role of the Janus kinase 2 (JAK2)/STAT3 signaling pathway in noise induce hearing loss using the pathway specific inhibitor, JSI-124. Mice were exposed to a moderately damaging level of loud sound revealing the phosphorylation of STAT3 tyrosine 705 residues and nuclear localization in many cell types in the inner ear including the marginal cells of the stria vascularis, type II, III, and IV fibrocytes, spiral ganglion cells, and in the inner hair cells. Treatment of the mice with the JAK2/STAT3 inhibitor before noise exposure reduced levels of phosphorylated STAT3 Y705. We performed auditory brain stem response and distortion product otoacoustic emission measurements and found increased recovery of hearing sensitivity at two weeks after noise exposure with JAK2/STAT3 inhibition. Performance of cytocochleograms revealed improved outer hair cell survival in JSI-124 treated mice relative to control. Finally, JAK2/STAT3 inhibition reduced levels of ROS detected in outer hair cells at two hours post noise exposure. Together, these findings demonstrate that inhibiting the JAK2/STAT3 signaling pathway is protective against noise-induced cochlear tissue damage and loss of hearing sensitivity.

Highlights

The generation of reactive oxygen species (ROS) is one of the underlying causes of noise-induced damage to tissues in the inner ear [1,2,3,4,5]
To assess whether Signal transducers and activators of transcription 3 (STAT3) phosphorylation is induced by noise exposure, mice were exposed to a loud sound protocol of 110 dB SPL, 4–48 kHz for 3 hours which results in a moderate amount of permanent cochlea damage and loss of hearing sensitivity
By immunohistochemical staining of paraffin sections, phosphorylated STAT3 was observed to be in the nuclei of many different cell types in the cochlea including in inner hair cells (IHCs), stria vascularis marginal cells (MC), the spiral ganglion cells (SG), and type II, III, and IV fibrocytes at 4 hours following noise exposure (Figure 2B)

Summary

Introduction

The generation of reactive oxygen species (ROS) is one of the underlying causes of noise-induced damage to tissues in the inner ear [1,2,3,4,5]. The cellular response to ROS-induced tissue injury in the cochlea is mediated by the actions of several oxidative stress-responsive signaling pathways including nuclear factor NF-kappa-B (NF-kB), p38 mitogen-activated protein kinase, and c-Jun-N-terminal kinase (JNK) [1,9,10]. Cell receptor binding by cytokines and growth factors including interleukin-6 (IL-6), IL-11, epidermal growth factor, and vascular endothelial growth factor can induce STAT3 phosphorylation by JAK and other tyrosine kinases resulting in increased transcription of an array of target genes [11,12,13]. Increasing evidence points to an important regulatory role for the JAK2/ STAT3 signaling pathway in cellular oxidative stress injury, as inhibition of JAK2/STAT3 signaling activity reduces hydrogen peroxide-induced cell death [16,17,18]. A transcriptionindependent mechanism for mediating increased NADPH oxidase ROS production by JAK2/STAT3, potentially through proteinprotein interactions, may exist [19]

Methods

Results

Conclusion