Editors' ChoiceHEARING LOSS

NLRP3, keep it down so we can hear

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Science Translational Medicine  13 Sep 2017:
Vol. 9, Issue 407, eaao6126
DOI: 10.1126/scitranslmed.aao6126


A gain-of-function mutation in NLRP3 is associated with cochlear inflammation and hearing loss.

There is a saying in medicine, “when you hear hoofbeats, think of horses not zebras,” but when it comes to human genetics, it's the zebras that inform us about the herd. In the recent work by Nakanishi and colleagues, a rare gain-of-function mutation may provide insight into a common disorder, sensorineural hearing loss.

Nakanishi et al. examined a family with three generations of autosomal dominant sensorineural hearing loss. Through genetic mapping and sequence analysis, they found that the pathogenic mutation in this family was a missense mutation in NLRP3. The NLRP3 inflammasome is an innate immune sensor that responds to microbial challenge and other stimuli by stimulating interleukin-1β (IL-1β) secretion. Different autosomal dominant mutations in NLRP3 also cause cryopyrin-associated periodic syndromes (CAPS), which are characterized by an array of recurrent inflammatory signs and symptoms. However, the family studied by Nakanishi and colleagues lacked clinical features associated with CAPS, leading to the hypothesis that NLRP3 might be active locally within the inner ear. On radiologic imaging, they found evidence of cochlear inflammation, and the subjects’ peripheral monocytes secreted high levels of IL-1β. The authors found that macrophage-like cells resident in normal mouse cochlea also express Nlrp3. Moreover, cells cultured from murine cochlear tissue secreted IL-1β in response to inflammasome-activating stimuli. In an additional family that had a systemic autoinflammatory phenotype, the same NLRP3 mutation (p.Arg918Gln) was also associated with sensorineural hearing loss. Four individuals from these families were treated with anakinra, an IL-1 receptor antagonist, resulting in improved hearing in the three younger individuals.

Overall, the authors’ work suggests that some cases of hearing loss may be due to the activation of innate immune pathways within the cochlea. It remains to be discovered whether the atypical clinical phenotype that appears to be associated with the p.Arg918Gln missense allele reflects something specific about cochlear biology or genetic or environmental modifiers. It will be exciting to see whether the NLRP3 inflammasome plays a role in more common causes of sensorineural hearing loss due to environmental stimuli such as infectious agents, chemicals, trauma, and aging.

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