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Proc Natl Acad Sci U S A. 2017 Sep 12;114(37):E7766-E7775. doi: 10.1073/pnas.1702946114. Epub 2017 Aug 28.

NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy.

Author information

1
Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892.
2
Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
3
Rheumatology Fellowship and Training Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892.
4
Rady Children's Hospital and Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093.
5
Office of the Clinical Director, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892.
6
Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892.
7
Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; kastnerd@mail.nih.gov griffita@nidcd.nih.gov.
8
Translational Autoinflammatory Disease Studies, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
9
Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892; kastnerd@mail.nih.gov griffita@nidcd.nih.gov.

Abstract

The NLRP3 inflammasome is an intracellular innate immune sensor that is expressed in immune cells, including monocytes and macrophages. Activation of the NLRP3 inflammasome leads to IL-1β secretion. Gain-of-function mutations of NLRP3 result in abnormal activation of the NLRP3 inflammasome, and cause the autosomal dominant systemic autoinflammatory disease spectrum, termed cryopyrin-associated periodic syndromes (CAPS). Here, we show that a missense mutation, p.Arg918Gln (c.2753G > A), of NLRP3 causes autosomal-dominant sensorineural hearing loss in two unrelated families. In family LMG446, hearing loss is accompanied by autoinflammatory signs and symptoms without serologic evidence of inflammation as part of an atypical CAPS phenotype and was reversed or improved by IL-1β blockade therapy. In family LMG113, hearing loss segregates without any other target-organ manifestations of CAPS. This observation led us to explore the possibility that resident macrophage/monocyte-like cells in the cochlea can mediate local autoinflammation via activation of the NLRP3 inflammasome. The NLRP3 inflammasome can indeed be activated in resident macrophage/monocyte-like cells in the mouse cochlea, resulting in secretion of IL-1β. This pathway could underlie treatable sensorineural hearing loss in DFNA34, CAPS, and possibly in a wide variety of hearing-loss disorders, such as sudden sensorineural hearing loss and Meniere's disease that are elicited by pathogens and processes that stimulate innate immune responses within the cochlea.

KEYWORDS:

cochlea; cryopyrin-associated periodic syndromes; hearing loss; inflammation; interleukin-1β

PMID:
28847925
PMCID:
PMC5604003
DOI:
10.1073/pnas.1702946114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: L.B. serves on the advisory boards for Sobi and Novartis. H.M.H. serves as a consultant for Sobi, a speaker and consultant for Novartis, and receives research support from Bristol-Myers Squibb. R.G.-M. receives research support from Sobi, Novartis, Regeneron, and Eli Lilly.

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