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

PLoS One. 2021 Oct 22;16(10):e0258977. doi: 10.1371/journal.pone.0258977. eCollection 2021.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Animals
  • Cochlea / immunology
  • Cochlea / metabolism*
  • Computational Biology
  • Disease Models, Animal
  • Gene Regulatory Networks / immunology*
  • Male
  • Mice
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Presbycusis / genetics
  • Presbycusis / immunology
  • Presbycusis / metabolism*
  • Up-Regulation*

Substances

  • NF-kappa B

Grant support

This work was supported by JSPS KAKENHI Grant Nos. JP19K18807 (principal investigator: S.F.) and JP20K09732 (S.K.). The Japan Society for the Promotion of Science (www.jsps.go.jp/) had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.