Upregulation of a nuclear factor-kappa B-interacting immune gene network in mice cochleae with age-related hearing loss

Abstract

Epidemiological data suggest that inflammation and innate immunity play significant roles in the pathogenesis of age-related hearing loss (ARHL) in humans. In this mouse study, real-time RT-PCR array targeting 84 immune-related genes revealed that the expressions of 40 genes (47.6%) were differentially regulated with greater than a twofold change in 12-month-old cochleae with ARHL relative to young control mice, 33 (39.3%) of which were upregulated. These differentially regulated genes (DEGs) were involved in functional pathways for cytokine–cytokine receptor interaction, chemokine signaling, TNF signaling, and Toll-like receptor signaling. An NF-κB subunit, Nfkb1, was upregulated in aged cochleae, and bioinformatic analyses predicted that NF-κB would interact with the genomic regulatory regions of eight upregulated DEGs, including Tnf and Ptgs2. In aging cochleae, major proinflammatory molecules, IL1B and IL18rap, were upregulated by 6 months of age and thereafter. Remarkable upregulations of seven immune-related genes (Casp1, IL18r1, IL1B, Card9, Clec4e, Ifit1, and Tlr9) occurred at an advanced stage (between 9 and 12 months of age) of ARHL. Immunohistochemistry analysis of cochlear sections from the 12-month-old mice indicated that IL-18r1 and IL-1B were localized to the spiral ligament, spiral limbus, and organ of Corti. The two NF-κB-interacting inflammatory molecules, TNFα and PTGS2, immunolocalized ubiquitously in cochlear structures, including the lateral wall (the stria vascularis and spiral ligament), in the histological sections of aged cochleae. IBA1-positive macrophages were observed in the stria vascularis and spiral ligament in aged mice. Therefore, inflammatory and immune reactions are modulated in aged cochlear tissues with ARHL.

UCHL1 regulated by Sp1 ameliorates cochlear hair cell senescence and oxidative damage

“…NF-κB signaling is key in the development of ARHL ( 17 ). Furthermore, UCHL1 is considered a downstream protein of NF-κB signaling ( 37 ) and is involved in numerous human diseases by regulating NF-κB signaling ( 38 , 39 ).…”

“…Recent literature has elucidated that Sp1 mediates cochlear cell apoptosis in hearing loss models ( 15 , 16 ). Furthermore, it has been also reported that NF-κB participates in the pathogenesis of ARHL via interaction with immune-associated genes ( 17 ).…”

Network pharmacology and experimental evidence reveal the protective mechanism of Yi-Qi Cong-Ming decoction on age-related hearing loss

“…A recent study by Uraguchi et al. ( 2021 ) analysed 84 immune-related genes expression in the cochlea of 12-month-old mice with ARHL as compared to the young control mice. They found around 40% of immune-related genes were upregulated in the aged cochlea, including PTGS2.…”

“… 2012 ; Uraguchi et al. 2021 ) incur the deleterious effects leading to this damage. Yi-qi Cong-ming (YQCM), a famous decoction composed of 8 herbs including Ginseng radix et rhizome ( Panax ginseng C.A.Mey.…”

AUF1 modulates apoptosis via regulating transcription and alternative splicing of immune response genes in auditory hair cells

“…A recent study reported the upregulation of major proin ammatory molecules, IL1B and IL18rap, in the cochleae of C57BL/6J mice older than 6 months of age. Moreover, the bioinformatic analyses indicated that the differentially regulated genes were involved in functional pathways for cytokine-cytokine receptor interaction, chemokine signaling, TNF signaling, and Toll-like receptor signaling (12). Moreover, previous investigations have reported immune function to be a critical factor in the development of presbycusis.…”