IGF-1 Haploinsufficiency Causes Age-Related Chronic Cochlear Inflammation and Increases Noise-Induced Hearing Loss

Abstract

Insulin-like growth factor 1 (IGF-1) deficiency is an ultrarare syndromic human sensorineural deafness. Accordingly, IGF-1 is essential for the postnatal maturation of the cochlea and the correct wiring of hearing in mice. Less severe decreases in human IGF-1 levels have been associated with other hearing loss rare genetic syndromes, as well as with age-related hearing loss (ARHL). However, the underlying mechanisms linking IGF-1 haploinsufficiency with auditory pathology and ARHL have not been studied. Igf1-heterozygous mice express less Igf1 transcription and have 40% lower IGF-1 serum levels than wild-type mice. Along with ageing, IGF-1 levels decreased concomitantly with the increased expression of inflammatory cytokines, Tgfb1 and Il1b, but there was no associated hearing loss. However, noise exposure of these mice caused increased injury to sensory hair cells and irreversible hearing loss. Concomitantly, there was a significant alteration in the expression ratio of pro- and anti-inflammatory cytokines in Igf1+/− mice. Unbalanced inflammation led to the activation of the stress kinase JNK and the failure to activate AKT. Our data show that IGF-1 haploinsufficiency causes a chronic subclinical proinflammatory age-associated state and, consequently, greater susceptibility to stressors. This work provides the molecular bases to further understand hearing disorders linked to IGF-1 deficiency.

Insulin-like Growth Factor 1 Signaling in Mammalian Hearing

“…Igf1r gene expression diminishes significantly from embryonic day E15.5 to postnatal day P5, but then increases slightly from P15 onwards [8,13,14], and is mainly localized in the outer hair cells [15]. Igf1r has been detected in the mouse cochlea at 12 months of age, with levels similar to those found at one month of age [14].…”

“…In the adult cochlea, Igf1 expression is reduced relative to embryonic stages [14] and it is mainly localized in Deiters' cells, whereas Igf2 expression is predominant in the pillar cells [8,15]. The expression of Igf1 and Igf2 can still be detected in 12-month-old mouse cochleae [14]. In contrast to the detailed information reported on IGFs expression in the developing and early postnatal cochlea, the information on the postnatal expression of the factors is scarce.…”

“…Following birth, Igf1r expression is restricted to the inner and outer spiral sulcus, the medial greater epithelial ridge cells, the supporting cells, the outer and inner hair cells and the basal cells of the stria vascularis, showing a complementary pattern to that of Igf1 [8,9,11,12]. Igf1r gene expression diminishes significantly from embryonic day E15.5 to postnatal day P5, but then increases slightly from P15 onwards [8,13,14], and is mainly localized in the outer hair cells [15]. Igf1r has been detected in the mouse cochlea at 12 months of age, with levels similar to those found at one month of age [14].…”

“…In the first weeks after birth (from P1 to P20), Igf1 expression in the early postnatal cochlea is mainly restricted to the marginal cells of the stria vascularis, the spiral limbus, the medial greater epithelial ridge cells, the supporting cells of the organ of Corti (inner sulcus, Claudius' and Hensen's cells), and a subpopulation of neurons of the spiral ganglion [8,[10][11][12]. Similar to Igf1, Igf2 expression remains high during development and falls dramatically after birth (from P1 to P30), becoming localized in the interdental cells and in the medial greater epithelial ridge cells [8,[12][13][14]. In the adult cochlea, Igf1 expression is reduced relative to embryonic stages [14] and it is mainly localized in Deiters' cells, whereas Igf2 expression is predominant in the pillar cells [8,15].…”

“…Similar to Igf1, Igf2 expression remains high during development and falls dramatically after birth (from P1 to P30), becoming localized in the interdental cells and in the medial greater epithelial ridge cells [8,[12][13][14]. In the adult cochlea, Igf1 expression is reduced relative to embryonic stages [14] and it is mainly localized in Deiters' cells, whereas Igf2 expression is predominant in the pillar cells [8,15]. The expression of Igf1 and Igf2 can still be detected in 12-month-old mouse cochleae [14].…”