LCCL peptide cleavage after noise exposure exacerbates hearing loss and is associated with the monocyte infiltration in the cochlea

Abstract

Acoustic trauma induces an inflammatory response in the cochlea, resulting in debilitating hearing function. Clinically, amelioration of inflammation substantially prevents noise-induced hearing loss. The Limulus factor C, Cochlin, and Lgl1 (LCCL) peptide plays an important role in innate immunity during bacteria-induced inflammation in the cochlea. We aimed to investigate the LCCL-induced innate immune response to noise exposure and its impact on hearing function.

Methods: We used Coch (encodes cochlin harboring LCCL peptide) knock-out and p.G88E knock-in mice to compare the immune responses before and after noise exposure. We explored their hearing function and hair cell degeneration. Moreover, we investigated distinct characteristics of immune responses upon noise exposure using flow cytometry and RNA sequencing.

Results: One day after noise exposure, the LCCL peptide cleaved from cochlin increased over time in the perilymph space. Both Coch^-/- and Coch^G88E/G88E mutant mice revealed more preserved hearing following acoustic trauma compared to wild-type mice. The outer hair cells were more preserved in Coch^-/- than in wild-type mice upon noise exposure. The RNA sequencing data demonstrated significantly upregulated cell migration gene ontology in wild-type mice than in Coch^-/- mice following noise exposure, indicating that the infiltration of immune cells was dependent on cochlin. Notably, infiltrated monocytes from blood (C11b⁺/Ly6G^-/Ly6C⁺) were remarkably higher in wild-type mice than in Coch^-/- mice at 1 day after noise exposure.

Conclusions: Noise-induced hearing loss was attributed to over-stimulated cochlin, and led to the cleavage and secretion of LCCL peptide in the cochlea. The LCCL peptide recruited more monocytes from the blood vessels upon noise stimulation, thus highlighting a novel therapeutic target for noise-induced hearing loss.

Keywords: AIED, Autoimmune Inner Ear Disease; Acoustic trauma, animal study, inflammatory response, LCCL peptide, noise-induced hearing loss, Abbreviations, ABR, auditory brainstem response; CCL2, C-C motif chemokine ligand 2; DEGs, differentially expressed genes; EDTA, ethylenediaminetetraacetic acid; IL-1β, interleukin-1β; IL-6, interleukin-6; KO, knock-out; LCCL, Limulus factor C, Cochlin, and Lgl1; NIHL, noise-induced hearing loss; RNA-seq, RNA sequencing; RT-PCR, real-time polymerase chain reaction; SDS, sodium dodecyl sulfate; SPL, sound pressure level; Tnf-α, tumor necrosis factor alpha.