Targeting Inflammatory Processes Mediated by TRPVI and TNF-α for Treating Noise-Induced Hearing Loss

Abstract

Noise trauma is the most common cause of hearing loss in adults. There are no known FDA approved drugs for prevention or rescue of noise-induced hearing loss (NIHL). In this study, we provide evidence that implicates stress signaling molecules (TRPV1, NOX3, and TNF-α) in NIHL. Furthermore, we provide evidence that inhibiting any one of these moieties can prevent and treat NIHL when administered within a window period. Hearing loss induced by loud noise is associated with the generation of reactive oxygen species (ROS), increased calcium (Ca2+) in the endolymph and hair cells, and increased inflammation in the cochlea. Increased (Ca2+) and ROS activity persists for several days after traumatic noise exposure (NE). Chronic increases in (Ca2+) and ROS have been shown to increase inflammation and apoptosis in various tissue. However, the precise role of Ca2+ up-regulation and the resulting inflammation causing a positive feedback loop in the noise-exposed cochlea to generate sustained toxic amounts of Ca2+ are unknown. Here we show cochlear TRPV1 dysregulation is a key step in NIHL, and that inflammatory TNF-α cytokine-mediated potentiation of TRPV1 induced Ca2+ entry is an essential mechanism of NIHL. In the Wistar rat model, noise produces an acute (within 48 h) and a chronic (within 21 days) increase in cochlear gene expression of TRPV1, NADPH oxidase 3 (NOX3) and pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX2). Additionally, we also show that H2O2 (100 μM) produces a robust increase in Ca2+ entry in cell cultures which is enhanced by TNF-α via the TRPV1 channel and which involves ERK1/2 phosphorylation. Mitigation of NIHL could be achieved by using capsaicin (TRPV1 agonist that rapidly desensitizes TRPV1. This mechanism is used in the treatment of pain in diabetic peripheral neuropathy) pretreatment or by inhibition of TNF-α with Etanercept (ETA), administered up to 7 days prior to NE or within 24 h of noise. Our results demonstrate the importance of the synergistic interaction between TNF-α and TRPV1 in the cochlea and suggest that these are important therapeutic targets for treating NIHL.

Treatment With Calcineurin Inhibitor FK506 Attenuates Noise-Induced Hearing Loss

“…In fact, ROS and inflammation may interplay (Fetoni et al, 2019), as accumulation of both ROS and cytokines has been well documented in noise-induced OHC death (Yamane et al, 1995;Shi et al, 2003;Yamashita et al, 2005;Fujioka et al, 2006;Le Prell et al, 2007;Dhukhwa et al, 2019;Fetoni et al, 2019;Frye et al, 2019). Our results support this notion as we show that the lipid peroxidation product 4-HNE, acting as a surrogate marker for ROS, is highly expressed in damaged OHCs in the basal turn after noise exposure that induces high-frequency hearing loss, while treatment with FK506 inhibits noise-induced accumulation of 4-HNE.…”

“…Loss of sensory hair cells in the cochlea, with outer hair cells (OHCs) being more vulnerable than inner hair cells (IHCs), has been well documented in humans and various animal models as a cause of permanent threshold shifts (PTS or permanent hearing loss) (Sha and Schacht, 2017;Wang and Puel, 2018). Although the molecular events occurring after noise exposure are highly complex, the notion of overload of calcium in the endolymph and hair cells, accumulation of reactive oxygen species (ROS), and increased cytokines contributing to the pathogenesis of noise-induced loss of sensory hair cells is well accepted (Ikeda and Morizono, 1988;Fridberger et al, 1998;Ohlemiller et al, 1999;Yamashita et al, 2004;Fujioka et al, 2006;Chen et al, 2012;Hill et al, 2016;Dhukhwa et al, 2019;Fettiplace and Nam, 2019).…”

“…Recently, a report showed that Nfatc3 (NFAT3) deficiency in mice attenuates ototoxicity by suppressing TNF-mediated hair cell apoptosis (Zhang et al, 2019). In fact, overproduction of both ROS and cytokines has been well documented in noise trauma with loss of OHCs (Yamane et al, 1995;Shi et al, 2003;Yamashita et al, 2005;Fujioka et al, 2006;Le Prell et al, 2007;Dhukhwa et al, 2019;Fetoni et al, 2019;Frye et al, 2019). It is speculated that ROS and inflammation have a complex interplay (Fetoni et al, 2019).…”

Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss

“…Furthermore, overexpression of RGS17 in the cochlea of naïve rats, using a viral vector, produced hearing loss. The pattern of high frequency hearing loss is somewhat less than that observed with cisplatin and noise exposures in our laboratory 51 . RGS17 mimicked cisplatin by increasing ABR thresholds and producing cochlear synaptopathy.…”

The immune response after noise damage in the cochlea is characterized by a heterogeneous mix of adaptive and innate immune cells

“…Neutrophils have a heterogeneous phenotype and play a role in directing the innate immune; therefore, further analysis might be insightful in the cochlear immune response to damage. The increased presence of immune cells in the noise-exposed cochlea suggests studying the definitive role of these immune cells in cochlear inflammation might be helpful in developing novel therapeutics targeting the inflammatory cascade 68 .…”