Journal Club: Loss of barrier function in small blood vessels of the cochlea as the underlying cause of hearing loss in the animal model of Lupus.

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Today's journal article

Zhao Z, Li A, Zhu Y, Cen S, Liu Q, Zhang Y, Fan H, Hou Z, Ma D, Liu D, Duan M, Qian X, Chai R, Wan G, Gao X. Blood-labyrinth barrier damage mediated by granzymes from cytotoxic lymphocytes results in hearing loss in systemic lupus erythematosus. 

Why I picked this article

This research contributes to some of the underlying pathologies for sensorineural hearing loss, associated with autoimmune diseases.

According to Arthritis New Zealand, systemic lupus erythematosus (SLE) is an autoimmune disease where your body's immune system attacks its own organs. The symptoms can occur in different organs, including skin rashes (skin), fatigue, joint pain, chest pain (lung, heart) etc. It is more common in women, and usually diagnosed young between 15 - 45 (https://www.arthritis.org.nz/newly-diagnosed/types-of-arthritis/lupus-sle). One of the possible symptoms is hearing loss, and the majority is sensorineural hearing loss. 

This research used an animal model for SLE and investigated the pathology in the cochlea, our hearing organ. 

Some of the research findings

Animal model:

  • Wild-type female C57BL/6 mice. 
  • Imiquimod is a small chemical that stimulates a receptor protein called Toll-like receptor 7.  
  • SLE model: Mice were administered imiquimod. Time points were 2, 4, 6, 8 and 10 weeks after imiquimod administration. 
  • Animal's hearing was evaluated with auditory brainstem response and distortion products otoacoustic emissions. 
  • Change in the cochlea was evaluated using a molecular profiling technique called single-cell RNAseq, as a way to profile cell makeup within the cochlea. 
  • Serpinb6b, an inhibitor for Gzma and Serpinb9, an inhibitor for Gzmb, were used to test the hypothesis that Gzmb may be important in SLE pathology in the cochlea. 
Part of Figure 1F, histology of kidney 2-6 weeks after imiquimod treatment. Zhao et al. (2025)

Finding: 

  • 4-weeks after imiquimod treatment, animals showed signs consistent with autoimmune disease, as well as some change in hearing. Hearing loss had occurred and stabilised by 6-8 weeks. Hearing loss was much more prominent and stable than that of Lpr mice, another popular SLE model, but did not have significant hearing loss at 21 weeks. 
  • The molecular profiling of the cochlea indicated loss of endothelial cells, cells that line the blood vessels. Similarly, other molecular biology data showed that some barriers in small blood vessels in the cochlea may be compromised in imiquimod-treated mice. 
  • Using tracer molecules (that can move within blood vessels and leak out if the blood vessels are damaged), small blood vessels in the imiquimod-treated mice cochlea showed signs of damage to capillaries. 
  • Deep dive into the single-cell RNAseq data showed that immune cells, NK-cells, were activated in the cochlea. Comparing between control and imiquimod-treatment group identified five key genes Ifng (IFN-γ), Ccl-5, Gzmb, Nkg7, and Ccl-4 as potentially important. 
  • Gzmb is a gene that makes granzyme B, related to toxicity in the cell. 
  • Gzmb inhibition in imiquimod-treated SLE model mitigated hearing loss.
Taken together, this research has shown the causal link between SLE > blood vessel damage in the cochlea, mediated by Gzmb, and inhibiting Gzmb can potentially reduce damage in the cochlea caused by SLE. 

Haruna's takeaway

Autoimmune diseases cause sensorineural hearing loss, and there seem to be more animal model-based studies now, which is very exciting for the field. I introduced another paper about Alport syndrome in another journal club, but this Lopus (SLE) is a systemic disease that also sometimes affects the eyes, and is also vulnerable to vascular barrier degeneration. Maybe many systemic inflammatory diseases will manifest in both hearing and vision systems, and perhaps this is where vision screening of capillaries in the retina may help predict the prognosis for hearing loss, too. 

I also noted the high-tech approach of using single-cell RNAseq, to estimate cellular changes in the cochlea, instead of conventional hair cell counting. It's much more comprehensive and powerful in the sense that hair-cell count will only look at hair cells, while the single-cell RNAseq will survey all cells. This is the way of the future.  The availability and cost of the platform have been a barrier for us to try, but perhaps we need to establish the pipeline in our group in near future. 

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This is Haruna's 23/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.