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Tlr2/4 Double Knockout Attenuates the Degeneration of Primary Auditory Neurons: Potential Mechanisms From
Quan Wang1,2, Yilin Shen1,2, Yi Pan1,2
1Department of Otolaryngology and Head and Neck Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
The transcriptomic landscape of mice with primary auditory neurons degeneration (PAND) indicates key pathways in its pathogenesis, including complement cascades, immune responses, tumor necrosis factor (TNF) signaling pathway, and cytokine-cytokine receptor interaction. Toll-like receptors (TLRs) are important immune and inflammatory molecules that have been shown to disrupt the disease network of PAND. In a PAND model involving administration of kanamycin combined with furosemide to destroy cochlear hair cells, Tlr 2/4 double knockout (DKO) mice had auditory preservation advantages, which were mainly manifested at 4-16 kHz. DKO mice and wild type (WT) mice had completely damaged cochlear hair cells on the 30th day, but the density of spiral ganglion neurons (SGN) in the Rosenthal canal was significantly higher in the DKO group than in the WT group. The results of immunohistochemistry for p38 and p65 showed that the attenuation of SGN degeneration in DKO mice may not be mediated by canonical Tlr signaling pathways. The SGN transcriptome of DKO and WT mice indicated that there was an inverted gene set enrichment relationship between their different transcriptomes and the SGN degeneration transcriptome, which is consistent with the morphology results. Core module analysis suggested that DKO mice may modulate SGN degeneration by activating two clusters, and the involved molecules include EGF, STAT3, CALB2, LOX, SNAP25, CAV2, SDC4, MYL1, NCS1, PVALB, TPM4, and TMOD4.
Insights
Toll-like receptors (TLRs) play a role in primary auditory neuron degeneration (PAND). Deleting TLRs 2 and 4 in mice protected auditory neurons, suggesting a novel therapeutic target for hearing loss.
Area of Science:
- Neuroscience
- Immunology
- Otolaryngology
Background:
- Primary auditory neuron degeneration (PAND) involves pathways like complement cascades, immune responses, and TNF signaling.
- Toll-like receptors (TLRs) are implicated in PAND pathogenesis and disease network disruption.
Purpose of the Study:
- To investigate the role of TLRs in PAND and their impact on spiral ganglion neuron (SGN) survival.
- To explore potential therapeutic strategies targeting TLRs for auditory neuron preservation.
Main Methods:
- A PAND mouse model was established using kanamycin and furosemide to induce cochlear hair cell damage.
- Toll-like receptor 2/4 double knockout (DKO) and wild-type (WT) mice were compared.
- Auditory function, SGN density, and molecular pathways (p38, p65, transcriptomics) were analyzed.
Main Results:
- DKO mice exhibited auditory preservation advantages, particularly at 4-16 kHz.
- Despite complete hair cell damage by day 30, DKO mice showed significantly higher SGN density than WT mice.
- SGN degeneration attenuation in DKO mice may not involve canonical TLR signaling pathways, with transcriptomic analysis revealing distinct gene expression patterns.
Conclusions:
- TLR2/4 knockout offers significant protection to spiral ganglion neurons in a PAND model.
- These findings suggest that modulating TLRs could be a viable strategy for treating hearing loss associated with PAND.
- Further research into the specific molecular mechanisms underlying TLR-mediated neuroprotection is warranted.
