Loss of sestrin 2 potentiates the early onset of age-related sensory cell degeneration in the cochlea

Abstract

Sestrin 2 (SESN2) is a stress-inducible protein that protects tissues from oxidative stress and delays the aging process. However, its role in maintaining the functional and structural integrity of the cochlea is largely unknown. Here, we report the expression of SESN2 protein in the sensory epithelium, particularly in hair cells. Using C57BL/6J mice, a mouse model of age-related cochlear degeneration, we observed a significant age-related reduction in SESN2 expression in cochlear tissues that was associated with early onset hearing loss and accelerated age-related sensory cell degeneration that progressed from the base toward the apex of the cochlea. Hair cell death occurred by caspase-8 mediated apoptosis. Compared to C57BL/6J control mice, Sesn2 KO mice displayed enhanced expression of proinflammatory genes and activation of basilar membrane macrophages, suggesting that loss of SESN2 function provokes the immune response. Together, these results suggest that Sesn2 plays an important role in cochlear homeostasis and immune responses to stress.

Inflammation associated with noise-induced hearing loss

“…This same innate capacity to adopt specific phenotypes also appears immanent in the macrophages of the cochlea, particularly those macrophages along the sensory epithelia. Prior studies of sensory epithelium macrophages indicate a site-dependent morphology for apical versus basal portions of the basilar membrane, suggesting a manifest immune capacity for cells of a dendritic shape versus amoeboid cells ( Yang et al , 2015 ; Frye et al , 2017 ; Zhang et al , 2017 ) mirroring that observed for microglia in the CNS ( Yin et al , 2017 ).…”

“…Moreover, infiltrated mononuclear phagocytes, including immature and less differentiated macrophages and monocytes, have been reported in many cochlear anatomic sites subsequent to cochlear stress. In ears that have undergone acoustic trauma, these infiltrated cells have been reported as present in the spiral ligament adjacent to fibrocytes ( Hirose et al , 2005 ; Tornabene et al , 2006 ), in the scala vestibuli, modiolus, and lateral wall ( Sautter et al , 2006 ; Wakabayashi et al , 2010 ; Du et al , 2011 ), Reissner's membrane ( Sautter et al , 2006 ), and immediately beneath the basilar membrane in the scala tympani cavity ( Frye et al , 2017 ; Zhang et al , 2017 ; Dong et al , 2018 ; Frye et al , 2018 ; Hu et al , 2018 ).…”

“…In addition to the very presence of these cells being observed within the various cochlear partitions outlined above, an apical-to-basal gradient in macrophage phenotype has been observed in cochlear sensory epithelia under steady-state conditions ( Yang et al , 2015 ; Frye et al , 2017 ). In particular, inner ear macrophages located immediately beneath the basilar membrane within the scala tympani cavity have received considerable attention, as these cells are the closest macrophages to sensory cells and the synapses for auditory spiral ganglia within the cochlea and are thus able to respond to stresses exerted on this tissue ( Yang et al , 2015 ; Frye et al , 2017 ; Zhang et al , 2017 ; Frye et al , 2018 ; Hu et al , 2018 ). While apically-located basilar membrane macrophages tend to display a ramified, dendritic morphology suggestive of resting and monitoring status, the basal turn of the basilar membrane presents with macrophages of an amoeboid morphology—a phenotype commonly seen in activated macrophages during noise-induced inflammation ( Yang et al , 2015 ).…”

mTOR as a central regulator of lifespan and aging

“…Finally, glutamine-dependent activation of mTORC1 is dependent on v-ATPase and also requires the adenosine diphosphate ribosylation factor 1 (ARF1) GTPase 119 . Although a number of studies show that alterations of these newly discovered mTOR regulators (for example, Sestrin2) may play a role in aging 120– 122 , their precise effects on life span and aging-related pathologies remain to be established.…”

Emerging Roles of Sestrins in Neurodegenerative Diseases: Counteracting Oxidative Stress and Beyond

“…Mice deficient in all three sestrins exhibit reduced postnatal survival associated with defective mTORC1 inactivation in multiple organs during neonatal fasting, thus revealing a non-redundant mechanism by which the sestrin family of guanine nucleotide dissociation inhibitors (GDIs) regulates the nutrient-sensing Rag GTPases to control mTORC1 signaling [73]. Sestrin2 knockout mice displayed enhanced expression of proinflammatory genes and activation of basilar membrane macrophages; these results suggest that sestrin2 plays an important role in cochlear homeostasis and immune responses to stress [74]. Other phenotypes of sestrin2 knockout mice included worsened hair cell loss in gentamicin-treated cochlear explants, implying an important role of sestrin2 in protecting hair cells against gentamicin [75].…”