Role of STAT3 in the loud sound‐induced stress response (651.19)

Abstract

Background: Signal transducers and activators of transcription 3 (STAT3) is a stress responsive transcription factor. STAT3 also possesses transcription‐independent activities of including direct regulation mitochondrial respiration and complex I activity as well as inhibition of autophagy under normal physiological conditions. Objective: To determine the role of STAT3 in the loud sound‐induced stress response in the inner ear. Methods and Results: Exposure of male CBA/CaJ mice (8 weeks old, n=5/group) to a moderately damaging level of sound (110 dB SPL, 4‐48 kHz, 3 hrs) resulted in phosphorylation and nuclear translocation of STAT3 in many cell types in the inner ear including auditory hair cells. Pharmacological inhibition of STAT3 activity with JSI‐124 prior to noise exposure revealed improved recovery of outer hair cell (OHC) function following noise exposure by Distortion Product Otoacoustic Emission measurement. In STAT3OHC‐/‐ mice, the OHCs appeared morphologically normal and alterations in markers of autophagy were observed. Conclusions: Loud sound exposure causes widespread STAT3 activation in the cochlea and STAT3 dependent VEGF upregulation. Inhibition of STAT3 proved protective of OHC function following noise exposure suggesting a role for the STAT3 mediated inflammatory response in OHC damage. STAT3 inhibited autophagic procesess in OHCs may be involved in the recovery function.Grant Funding Source: NIDCD R01 DC000105