Journal Club: Macrophage may help recovery of synapses and hearing after exposure to noise.

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Today's journal article

Gawande DY, Murali SV, Thakur SS, Rahmatulloev S, Nicolaisen EJ, Batalkina L, Cardona AE, Kaur T. "Genetic polymorphisms in human CX3CR1-mediated macrophage dysregulation are associated with the worsening of hearing loss and cochlear degeneration after noise trauma: a study in a humanized mouse model."

Why I picked this article

This study uses a genetically modified mouse model to explore the potential link between macrophages and susceptibility to developing hearing loss. 

Macrophages are very special immune cells found in most organs. Macrophages can be sitting quietly as part of surveillance, and then get activated upon encounter with a foreign body or pathogen. Macrophages exist in our hearing organ, the cochlea, and they are thought to play many defence roles. 

Previous research found that, the large majority of macrophages in the cochlea use a protein called CX3CR1, also called the fractalkine receptor, on their surface. CX3CR1 communicate with another protein called CX3CL1, which is found in the auditory neuron and hair cells. This led to the idea that macrophages and auditory neurons/hair cells communicate with each other by CX3CR1 and CX3CL1 to protect the cochlear environment, which was the focus of this research publication. 

I picked this publication today to learn more about CX3CR1 and macrophages. I am interested in macrophages through our previous work on P2X4 receptors, which appear to be expressed in macrophages. 

(made using biorender.com)  

Some of the research findings

Mouse models:

  • CX3CR1-wild type (WT) (JAX stock number: 000664)
  • CX3CR1-knockout (KO) (JAX stock number: 005582)
  • hCX3CR1I249/ M280 (= mice expressing human CX3CR1 variants) 

Treatment groups: Animals from the above genetic backgrounds were either:

  • Unexposed to noise (2-hour exposure to 8–16 kHz noise, 93 dB SPL), mix gender, p35-49
  • Exposed to excessive noise, mixed gender, p35-49

Findings:

  • At baseline, three groups of mice showed no difference in ABR thresholds (= same baseline hearing)
  • 1 day after the noise exposure: all three groups lost good hearing, but the hCX3CR1I249/ M280 group had slightly worse hearing than the other two groups.
  • Two weeks after the noise exposure, WT mice's hearing had almost recovered, but KO and hCX3CR1I249/ M280 had worse hearing. 
  • Also, two weeks after the noise exposure, the number of synapses in inner hair cells in KO and hCX3CR1I249/ M280 were less than the baseline or WT mouse cochlea. 
  • In the control group, macrophages increase in number after noise-exposure but this was not the case in KO and hCX3CR1I249/ M280 mice.
Together, the study suggests that the CX3CR1 protein is important in allowing normal response of macrophages in response to noise, and helps the cochlea recover from the noise-exposed temporary hearing loss. 

Haruna's takeaway

It's nice seeing a demonstration of the impact of CX3CR1 protein function on recovery after noise. The fact that the hearing of the KO animal is normal at the baseline is the interesting part, as it shows the importance of signalling as you are exposed to environmental risk factors for hearing loss. The implication is that even if you have polymorphism for this receptor, you may not necessarily have hearing loss from birth, but rather, develop hearing loss at an earlier age/at an accelerated rate as you start to be exposed to excessive sounds. 

This was mentioned in the literature, but the counterpart to the CX3CR1 receptor, CX3CL1, is found in auditory neurons and hair cells. This is so interesting, and I wonder where (which part of the neuron or which surface of hair cells) you find CX3CL1. It will be really cool, for example, if someone can demonstrate using super-resolution imaging that the feet of a macrophage with CX3CR1 make contact with the CX3CL1 on the hair cell. Maybe the study exists already, I will need to have a look. 

Overall, I love the concept of active and dynamic cells and cell-to-cell cross-talk happening in the cochlea. Very basic biology, and yet fascinating. 

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This is Haruna's 5/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.