Analysis for the mechanism of sensorineural hearing loss caused by cochlear autoinflammation

• Project/Area Number: 17K11324
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Otorhinolaryngology
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: Nakanishi Hiroshi 浜松医科大学, 医学部, 助教 (20444359)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 免疫応答 / 蝸牛 / 難聴 / 自然免疫

Outline of Final Research Achievements

Gain of function mutations of NLRP3 induce the activation of NLRP3 inflammasome, resulting in the secretion of proinflammatory cytokine, interleukin-1 beta, to cause systemic inflammatory diseases, cryopyrin associated periodic syndromes. We revealed that a gain of function mutation of NLRP3 also cause non-syndromic hearing loss. We hypothesized that the hearing loss was caused by the activation of NLRP3 inflammasome mainly in the cochleae. We revealed that NLRP3 inflammasome was activated in tissue-resident macrophage-like cells in the wild type mouse cochleae, supporting the hypothesis.

Academic Significance and Societal Importance of the Research Achievements

蝸牛には組織マクロファージなどの免疫担当細胞は存在せず、難聴にも関与しないと考えられてきた。この研究は、蝸牛内に組織マクロファージが存在し、その細胞内に能動免疫の中心的役割を果たすNLRP3インフラマソームが存在すること、さらに蝸牛内炎症が難聴に関与することを明らかにした点で大変画期的であると思われる。この研究成果は英文誌に掲載された。

Research Products

• [Journal Article] Genetic hearing loss associated with autoinflammation. (2020)
  • Author(s): Nakanishi H, Prakash P, Ito T, Kim HJ, Harrow D, Roux I, Hosokawa S, Griffith AJ
  • Journal Title: Front Neurol Volume: 11 Pages: 141-141
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 原著 当院で経験した中耳放線菌症3例の検討 (2019)
  • Author(s): 中西啓, 水田邦博, 星野知之, 遠藤志織, 大和谷崇, 細川誠二, 峯田周幸
  • Journal Title: 耳鼻咽喉科・頭頸部外科 Volume: 91 Issue: 6 Pages: 483-488
  • DOI: 10.11477/mf.1411202104
  • ISSN: 0914-3491, 1882-1316
  • Year and Date: 2019-05-20
  • Peer Reviewed
• [Journal Article] Comprehensive analysis of syndromic hearing loss patients in Japan (2019)
  • Author(s): Ideura Michie、Nishio Shin-ya、Sugahara Kazuma、他
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 11976-11976
  • DOI: 10.1038/s41598-019-47141-4
  • Peer Reviewed / Open Access
• [Journal Article] Risk Factors and Prognostic Factors of Hearing Impairment in Neonatal Intensive Care Unit-Treated Infants. (2019)
  • Author(s): Umehara T, Hosokawa S*, Kita JY, Takahashi G, Okamura J, Nakanishi H, Hosokawa K, Kyou K, Hayashi Y, Mineta H
  • Journal Title: Audiol Neurootol Volume: 24 Issue: 2 Pages: 84-89
  • DOI: 10.1159/000500316
  • Peer Reviewed
• [Journal Article] 小児・成人・高齢者、それぞれの耳管． (2019)
  • Author(s): 中西啓, 水田邦博, 峯田周幸
  • Journal Title: JOHNS Volume: 35 Pages: 411-414
• [Journal Article] 慢性鼓膜縁に対する処置． (2019)
  • Author(s): 中西啓，水田邦博，峯田周幸
  • Journal Title: JOHNS Volume: 35 Pages: 112-114
• [Journal Article] Auditory Evaluation in a Patient with HDR Syndrome (2019)
  • Author(s): 近藤玄樹*, 中西啓, 鈴木克佳, 袴田桂, 細川誠二, 峯田周幸, 岡村純
  • Journal Title: Practica Oto-Rhino-Laryngologica Volume: 112 Issue: 6 Pages: 359-363
  • DOI: 10.5631/jibirin.112.359
  • NAID: 130007657418
  • ISSN: 0032-6313, 1884-4545
  • Peer Reviewed
• [Journal Article] Excision Challenges in the First Reported Case of an Ameloblastoma Found in the Middle Ear (2018)
  • Author(s): Yamatodani T, Misawa K, Endo S, Nakanishi H, Hosokawa S, Mineta H
  • Journal Title: Journal of International Advanced Otology Volume: 10 Issue: 1 Pages: 1-5
  • DOI: 10.5152/iao.2019.5433
  • Peer Reviewed / Open Access
• [Journal Article] Tmc2 expression partially restores auditory function in a mouse model of DFNB7/B11 deafness caused by loss of Tmc1 function. (2018)
  • Author(s): Nakanishi H, Kurima K, Pan B, Wangemann P, Fitzgerald TS, Geleoc GS, Holt JR, Griffith AJ.
  • Journal Title: Sci Rep Volume: 14 Issue: 1 Pages: 12125-12125
  • DOI: 10.1038/s41598-018-29709-8
  • Peer Reviewed / Open Access
• [Journal Article] A Case of Actinomycosis of the Middle Ear (2018)
  • Author(s): 中西啓, 遠藤志織, 大和谷崇, 細川誠二, 峯田周幸．
  • Journal Title: Practica Oto-Rhino-Laryngologica Volume: 111 Issue: 10 Pages: 669-674
  • DOI: 10.5631/jibirin.111.669
  • NAID: 130007492782
  • ISSN: 0032-6313, 1884-4545
  • Peer Reviewed
• [Journal Article] A case of improved hearing with cochlear implantation in Gaucher disease type 1 (2018)
  • Author(s): Endo S, Mizuta K, Yamatodani T, Nakanishi H, Hosokawa K, Misawa K, Hosokawa S, Mineta H.
  • Journal Title: Auris Nasus Larynx Volume: 45 Issue: 3 Pages: 603-607
  • DOI: 10.1016/j.anl.2017.05.013
  • Peer Reviewed / Open Access
• [Journal Article] Hyperbaric Oxygen Therapy as Concurrent Treatment with Systemic Steroids for Idiopathic Sudden Sensorineural Hearing Loss: A Comparison of Three Different Steroid Treatments. (2018)
  • Author(s): Hosokawa S, Hosokawa K, Takahashi G, Sugiyama K, Nakanishi H, Takebayashi S, Mineta H.
  • Journal Title: Audiol Neurootol Volume: 233 Issue: 3 Pages: 145-151
  • DOI: 10.1159/000493083
  • Peer Reviewed
• [Journal Article] Gradual Symmetric Progression of DFNA34 Hearing Loss Caused by an NLRP3 Mutation and Cochlear Autoinflammation. (2018)
  • Author(s): Nakanishi H, Kawashima Y, Kurima K, Muskett JA, Kim HJ, Brewer CC, Griffith AJ.
  • Journal Title: Otol Neurotol Volume: 39 Issue: 3 Pages: e181-e185
  • DOI: 10.1097/mao.0000000000001715
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pathology and Treatment of Patulous Eustachian Tube in Patients with and without Habitual Sniffing (2018)
  • Author(s): 遠藤志織, 水田邦博, 高橋吾郎, 中西啓, 細川久美子, 大和谷崇, 三澤清, 細川誠二, 峯田周幸．
  • Journal Title: Practica Oto-Rhino-Laryngologica Volume: 111 Issue: 3 Pages: 161-166
  • DOI: 10.5631/jibirin.111.161
  • NAID: 130006407220
  • ISSN: 0032-6313, 1884-4545
  • Peer Reviewed
• [Journal Article] NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy. (2017)
  • Author(s): Nakanishi H, Kawashima Y, Kurima K, Chae JJ, Ross AM, Pinto-Patarroyo G, Patel SK, Muskett JA, Ratay JS, Chattaraj P, Park YH, Grevich S, Brewer CC, Hoa M, Kim HJ, Butman JA, Broderick L, Hoffman HM, Aksentijevich I, Kastner DL, Goldbach- Mansky R, Griffith AJ.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 114 Issue: 37
  • DOI: 10.1073/pnas.1702946114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Case of Branchio-oto Syndrome Caused by <i>EYA1</i> Mutation (2017)
  • Author(s): 中西啓, 遠藤 志織, 大和谷 崇, 峯田 周幸．
  • Journal Title: Practica Oto-Rhino-Laryngologica Volume: 110 Issue: 9 Pages: 629-635
  • DOI: 10.5631/jibirin.110.629
  • NAID: 130006038399
  • ISSN: 0032-6313, 1884-4545
  • Peer Reviewed
• [Journal Article] Evaluation of the clinical findings in patients with Usher syndrome type 1 (2017)
  • Author(s): 中西啓, 岩崎聡, 遠藤志織, 大和谷崇, 水田邦博, 峯田周幸．
  • Journal Title: AUDIOLOGY JAPAN Volume: 60 Issue: 6 Pages: 484-491
  • DOI: 10.4295/audiology.60.484
  • NAID: 130006489409
  • ISSN: 0303-8106, 1883-7301
  • Peer Reviewed
• [Journal Article] Clinical analysis of secondary acquired cholesteatoma. (2017)
  • Author(s): Yamatodani T, Mizuta K, Endo S, Nakanishi H, Takahashi G, Misawa K, Hosokawa S, Mineta H.
  • Journal Title: Arch Gen Intern Med Volume: 1 Pages: 10-14
  • Peer Reviewed / Open Access
• [Journal Article] A Case of Multilocular Temporomandibular Joint Ganglion Manifesting as an External Auditory Canal Mass (2017)
  • Author(s): 大和谷崇, 中西啓, 遠藤志織, 小黒美樹, 三澤清, 峯田周幸．
  • Journal Title: Practica Oto-Rhino-Laryngologica Volume: 110 Issue: 8 Pages: 525-529
  • DOI: 10.5631/jibirin.110.525
  • NAID: 130005875921
  • ISSN: 0032-6313, 1884-4545
  • Peer Reviewed
• [Presentation] NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34. (2019)
  • Author(s): Nakanishi H, Mineta H, Griffith AJ
  • Organizer: 15th Japan-Taiwan Conference on Otolaryngology-Head and Neck Surgery
  • Int'l Joint Research / Invited
• [Presentation] マウス蝸牛有毛細胞におけるTmc1 とTmc2 の機能解析． (2019)
  • Author(s): 中西啓, 峯田周幸
  • Organizer: 第120回日本耳鼻咽喉科学会総会・学術講演会
• [Presentation] 当院における先天性耳小骨形態異常症例の検討． (2019)
  • Author(s): 中西啓，峯田周幸
  • Organizer: 第14回小児耳鼻咽喉科学会総会・学術講演会
• [Presentation] マウス蝸牛組織における自然免疫応答の検討． (2019)
  • Author(s): 中西啓，峯田周幸
  • Organizer: 第29回日本耳科学会総会・学術講演会
• [Presentation] PAX3遺伝子変異にて発症したWaardenburg症候群例． (2018)
  • Author(s): 中西啓, 峯田周幸．
  • Organizer: 第13回日本小児耳鼻咽喉科学会総会・学術講演会
• [Presentation] 非症候群性難聴DFNA34の原因遺伝子同定および病態解． (2018)
  • Author(s): 中西啓，川島慶之，峯田周幸．
  • Organizer: 第28回日本耳科学会総会・学術講演会
• [Presentation] NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34. (2018)
  • Author(s): Nakanishi H, Mineta H, Griffith AJ.
  • Organizer: 日本人類遺伝学会第63回大会
• [Presentation] 小児難聴：原因と言語発達への影響． (2018)
  • Author(s): 中西啓, 峯田周幸．
  • Organizer: 第184回日耳鼻神奈川県地方部会学術講演会
  • Invited
• [Presentation] 小児難聴：原因と言語発達への影響． (2018)
  • Author(s): 中西啓, 峯田周幸．
  • Organizer: 静岡県耳鼻咽喉科医会学術講演
  • Invited
• [Presentation] Transgenic Tmc2 expression partially rescues auditory function in a mouse model of DFNB7/B11 deafness. (2018)
  • Author(s): Nakanishi H, Kurima K, Pan B, Wangemann, P; Fitzgerald TS, Holt JR, Griffith AJ.
  • Organizer: ARO 41st Annual MidWinter Meeting
  • Int'l Joint Research
• [Presentation] 結核性中耳炎例． (2017)
  • Author(s): 中西啓, 泉智沙子, 遠藤志織, 大和谷崇, 峯田周幸．
  • Organizer: 第118回日本耳鼻咽喉科学会通常総会・学術講演会
• [Presentation] Branchio-Oto症候群例． (2017)
  • Author(s): 中西啓，遠藤志織，大和谷崇，峯田周幸．
  • Organizer: 第12回日本小児耳鼻咽喉科学会総会・学術講演会
• [Presentation] TECTA遺伝子変異により発症した非症候群性難聴家系における聴力像の検討． (2017)
  • Author(s): 中西啓，遠藤志織，大和谷崇，峯田周幸．
  • Organizer: 第62回日本聴覚医学会総会・学術講演会
• [Presentation] 当院で経験した中耳放線菌症2症例の検討． (2017)
  • Author(s): 中西啓，水田邦博，遠藤志織，大和谷崇，峯田周幸．
  • Organizer: 第27回日本耳科学会総会・学術講演