Deficiency of Duffy Antigen Receptor for Chemokines Ameliorated Cochlear Damage From Noise Exposure

Abstract

Cochlear inflammatory response to various environmental insults, including acoustic and ototoxic overexposures, has been increasingly become a topic of interest. As the immune response is associated with both pathology and protection, targeting specific components of the immune response is expected to dissect the relationships between cellular damage and inflammation-associated protection and repair in the cochlea. Duffy antigen receptor for chemokines (DARC) is a member of a group of atypical chemokine receptors, and essential for chemokine-regulated leukocyte/neutrophil trafficking during inflammation. Previous studies have reported that Darc deficiency alters chemokine bioavailability and leukocyte homeostasis, leading to significant anti-inflammatory effects in tissues following injury. In this study, we have used Darc knockout mice to determine the impact of a deficiency in this gene on cochlear development, as well as function in cochlea subjected to various stresses. We observed that DARC is not required for normal development of cochlear function, as evidenced by typical hearing sensitivity in juvenile Darc-KO mice, as compared to wild type (WT) C57BL/6 mice. However, Darc-KO mice exhibited improved hearing recovery after intense noise exposure when compared to wild-type. The auditory brainstem response (ABR) threshold shift between KO and WT mice was most obvious at 1-week post-noise exposure. At cochlear locations above the frequency range of the energy band of damaging noise, both hair cell survival and ribbon synapse density were improved in Darc deficient animals. In addition, the mRNA levels of some major inflammatory effectors, including Mcp-1 and Gdf15, were altered in Darc-KO mice compared to control mice at 1, 3 and 7 days post-noise exposure. These data collectively suggest that the normal Darc-dependent inflammatory response slows down the process of hearing recovery, and exacerbates cellular damage in the cochlea after noise exposure.

Intratympanic Lipopolysaccharide Elevates Systemic Fluorescent Gentamicin Uptake in the Cochlea

“…For instance, moderate noise exposure can result in suprathreshold hearing deficit without obvious HC loss 21,23 . Furthermore, the cochlear immune activity likely has a unique role in cochlear synaptopathy 24,25 . Thus, it is a legitimate question whether i.t .…”

“… 21 , 23 Furthermore, the cochlear immune activity likely has a unique role in cochlear synaptopathy. 24 , 25 Thus, it is a legitimate question whether i.t . LPS could lead to synaptic damage to some extent, though subsequent work is warranted.…”

Cytokine Levels in Inner Ear Fluid of Young and Aged Mice as Molecular Biomarkers of Noise-Induced Hearing Loss

“…Here we report that DARC is expressed in the SGNs and inner ear sensorineural epithelium, primarily in the inner hair cells, outer pillar cells, and the third row of Deiters cells. While the precise physiological role of DARC in the inner ear remains to be determined, a recent study of Darc knockout mice reported that DARC deficiency affords improved hearing recovery after intense noise exposure when compared to wild type mice (56). However, we did not detect a striking difference in the immunostaining intensity for cellular distribution of DARC in unexposed vs. noise-exposed animals.…”

Macrophages in Noise-Exposed Cochlea: Changes, Regulation and the Potential Role

“…For a group of atypical chemokine receptor, Duffy antigen receptor for chemokines (DARC) is essential for chemokine-regulated inflammatory cells trafficking. Darc-KO mice exhibited improved hearing recovery after intense noise exposure when compared to control mice [36], but the potential relationship between DARC and cochlear macrophages after noise require additional studies.…”