Mechanisms of Inflammasome Regulation by Autoimmune Responses and Microbial Infection in Benign Prostatic Hyperplasia

• Project/Area Number: 19K09733
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Fukushima Medical University
• Principal Investigator: Kojima Yoshiyuki 福島県立医科大学, 医学部, 教授 (60305539)
• Co-Investigator(Kenkyū-buntansha): 秦 淳也 福島県立医科大学, 医学部, 助教 (00769606) ; 錫谷 達夫 福島県立医科大学, 医学部, 教授 (40196895) ; 関根 英治 福島県立医科大学, 医学部, 教授 (40363759) ; 羽賀 宣博 福岡大学, 医学部, 教授 (50586617) ; 赤井畑 秀則 福島県立医科大学, 医学部, 講師 (70644178) ; 石橋 啓 福島県立医科大学, 医学部, 博士研究員 (90347211)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 前立腺肥大症 / 自己免疫疾患 / 補体 / 細菌 / 微生物 / 細胞増殖 / 自己免疫反応 / オートファジー

Outline of Research at the Start

自然免疫の補体系は、古典経路・レクチン経路・第二経路を通じて活性化し、自己抗原反応や病原微生物の排除に作用するが、最近私達は補体の活性化が、BPH発症に関与していることを突き止めた。そこで本研究では、これまでの成果を踏まえ、研究 I：BPHにおける補体関連分子の発現機能解析と胎児性自己抗原を標的とした自己免疫応答システムの解明　研究 II：BPHにおける微生物の探索とオートファジーによるインフラマソーム制御機構の解明　という2つの研究テーマを掲げ、BPHの細胞増殖ネットワーク制御機構の解明と新しい創薬開発に向けた基礎的研究を行うこととした。

Outline of Final Research Achievements

Functional analysis of complement expression and identification of autoantigens were performed using a rat model of BPH. We found that immune complexes with annexin, Hsp90, α-SMA, and β-actin as autoantigens activate the entire complement system, mainly the classical pathway, and amplify inflammation, suggesting that autoimmune reactions may be involved in the pathogenesis of BPH. We also generated factor B knockout BPH rats and analyzed the functional expression of complement molecules. Furthermore, we demonstrated the presence of bacteria in the human prostate gland and correlated this with glandular epithelial hyperplasia in the prostate gland.

Academic Significance and Societal Importance of the Research Achievements

前立腺肥大症（BPH）は、性ホルモンによって様々な増殖因子・サイトカイン・神経伝達物質が刺激され、上皮-間質間相互作用の中で誘導されると考えられている。私達は前立腺増殖過程において、炎症や増殖因子・サイトカイン・各種シグナル伝達系が関与することを報告してきたが、それらを誘導する発症要因に関してはほとんど明らかになっていない。私たちは、前立腺肥大症が自己免疫疾患のひとつであるという仮説を立て、研究を進めていたが、細菌感染がそれを誘導する可能性、抗原抗体反応による免疫複合体が補体経路を活性化する可能性を突き止め、その機序を明確にしつつある。

Research Products

• [Journal Article] The Firmicutes/Bacteroidetes ratio of the human gut microbiota is associated with prostate enlargement. (2021)
  • Author(s): Takezawa K, Fujita K, Matsushita M, Motooka D, Hatano K, Banno E, Shimizu N, Takao T, Takada S, Okada K, Fukuhara S, Kiuchi H, Uemura H, Nakamura S, Kojima Y, Nonomura N.
  • Journal Title: Prostate Volume: 81 Issue: 16 Pages: 1287-1293
  • DOI: 10.1002/pros.24223
  • Peer Reviewed / Open Access
• [Journal Article] Upregulation of glucocorticoid receptor‐mediated glucose transporter 4 in enzalutamide‐resistant prostate cancer (2021)
  • Author(s): Hoshi Seiji、Meguro Satoru、Imai Hitomi、Matsuoka Yuta、Yoshida Yuki、Onagi Akihumi、Tanji Ryo、Honda‐Takinami Ruriko、Matsuoka Kanako、Koguchi Tomoyuki、Hata Junya、Sato Yuichi、Akaihata Hidenori、Kataoka Masao、Ogawa Soichiro、Kojima Yoshiyuki
  • Journal Title: Cancer Science Volume: 112 Issue: 5 Pages: 1899-1910
  • DOI: 10.1111/cas.14865
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association Between Surgical Stress and Biochemical Recurrence After Robotic Radical Prostatectomy (2021)
  • Author(s): Meguro Satoru、Haga Nobuhiro、Imai Hitomi、Yoshida Yuki、Takinami-Honda Ruriko、Matsuoka Kanako、Hoshi Seiji、Hata Junya、Sato Yuichi、Akaihata Hidenori、Kataoka Masao、Ogawa Soichiro、Kojima Yoshiyuki
  • Journal Title: JSLS : Journal of the Society of Laparoscopic & Robotic Surgeons Volume: 25 Issue: 1 Pages: e2020.00078-e2020.00078
  • DOI: 10.4293/jsls.2020.00078
  • Peer Reviewed
• [Journal Article] l-Theanine Protects Bladder Function by Suppressing Chronic Sympathetic Hyperactivity in Spontaneously Hypertensive Rat (2021)
  • Author(s): Matsuoka Kanako、Akaihata Hidenori、Hata Junya、Tanji Ryo、Honda-Takinami Ruriko、Onagi Akifumi、Hoshi Seiji、Koguchi Tomoyuki、Sato Yuichi、Kataoka Masao、Ogawa Soichiro、Kojima Yoshiyuki
  • Journal Title: Metabolites Volume: 11 Issue: 11 Pages: 778-778
  • DOI: 10.3390/metabo11110778
• [Journal Article] The effect of β3-adrenoceptor gene polymorphisms on lower urinary tract function in males (2021)
  • Author(s): Haga Nobuhiro、Okabe Yu、Miyazaki Takeshi、Tsubouchi Kazuna、Akaihata Hidenori、Hata Junya、Honda Ruriko、Matsuoka Kanako、Ogawa Soichiro、Kojima Yoshiyuki
  • Journal Title: World Journal of Urology Volume: 39 Issue: 8 Pages: 3035-3040
  • DOI: 10.1007/s00345-020-03531-2
• [Journal Article] Prevalence and predictors of postoperative detrusor underactivity after robot‐assisted radical prostatectomy: A prospective observational study (2021)
  • Author(s): Hata Junya、Onagi Akifumi、Tanji Ryo、Honda‐Takinami Ruriko、Matsuoka Kanako、Hoshi Seiji、Sato Yuichi、Ogawa Soichiro、Kataoka Masao、Haga Nobuhiro、Kojima Yoshiyuki
  • Journal Title: International Journal of Urology Volume: 28 Issue: 7 Pages: 734-740
  • DOI: 10.1111/iju.14549
• [Journal Article] Usefulness of the mayo adhesive probability score as a predictive factor for renal function deterioration after partial nephrectomy: a retrospective case?control study (2021)
  • Author(s): Hata Junya、Matsuoka Yuta、Onagi Akifumi、Honda-Takinami Ruriko、Matsuoka Kanako、Sato Yuichi、Akaihata Hidenori、Ogawa Soichiro、Kataoka Masao、Hosoi Takayuki、Kojima Yoshiyuki
  • Journal Title: International Urology and Nephrology Volume: 53 Issue: 11 Pages: 2281-2288
  • DOI: 10.1007/s11255-021-02986-5
• [Journal Article] Morphological change and characteristics of myofibroblasts during the growth process of benign prostatic hyperplasia (2020)
  • Author(s): Hata J, Tanji R, Onagi A, Honda-Takinami R, Matsuoka K, Hoshi S, Sato Y, Akaihata H, Haga N, Kojima Y.
  • Journal Title: Int J Urol Volume: 27 Issue: 8 Pages: 676-683
  • DOI: 10.1111/iju.14265
  • Peer Reviewed
• [Journal Article] Complement activation by autoantigen recognition in the growth process of benign prostatic hyperplasia (2019)
  • Author(s): Hata Junya、Machida Takeshi、Matsuoka Kanako、Hoshi Seiji、Akaihata Hidenori、Hiraki Hiroyuki、Suzuki Toshiyuki、Ogawa Soichiro、Kataoka Masao、Haga Nobuhiro、Ishibashi Kei、Homma Yoshimi、Sekine Hideharu、Kojima Yoshiyuki
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 00-00
  • DOI: 10.1038/s41598-019-57001-w
  • Peer Reviewed / Open Access
• [Presentation] Developmental mechanism of benign prostatic hyperplasia by NLRP3 inflammasome thorough complement pathway (2021)
  • Author(s): Hata Junya, Endo Yu, Hasegawa Akihisa, Harigane Yuki, Makabe Syunta, Yaginuma Kei, Matsuoka Kanako, Onagi Akifumi, Koguchi Tomoyuki, Sato Yuichi, Akaihata Hidenori, Kataoka Masao, Ogawa Soichiro, Kojima Yoshiyuki
  • Organizer: The 2021 Annual Meeting of the American Urological Association
  • Int'l Joint Research
• [Presentation] Long-term prognosis of lower urinary tract function after robot-assisted radical prostatectomy in patients with preoperatively low bladder contractility. (2021)
  • Author(s): Hata Junya, Endo Yu, Hasegawa Akihisa, Harigane Yuki, Makabe Syunta, Yaginuma Kei, Matsuoka Kanako, Onagi Akihumi, Koguchi Tomoyuki, Sato Yuichi, Akaihata Hidenori, Kataoka Masao, Ogawa Soichiro, Kojima Yoshiyuki.
  • Organizer: The 2021 Annual Meeting of the American Urological Association.
  • Int'l Joint Research
• [Presentation] Clinical characteristics of male LUTS patients without vesical adaptation response to diuresis using 3-day sensory-related frequency volume charts. (2021)
  • Author(s): Matsuoka Kanako, Akaihata Hidenori, Hakozaki Yusuke, Kirihana Yusuke, Natsuya Hiroki, Kumekawa Tomoyuki, Yoshioka Shunsuke, Imai Hitomi, Onagi Akifumi, Koguchi Tomoyuki, Hata Junya, Yuichi Sato, Masao Kataoka, Yoshiyuki Kojima
  • Organizer: The 15th Pan-Pacific Continence Society Meeting
  • Int'l Joint Research
• [Presentation] Impact of nocturnal enuresis on QOL after robot-assisted radical prostatectomy. (2021)
  • Author(s): Honda-Takinami Ruriko, Kataoka Masao, Yaginuma Kei, Hasegawa Akihisa, Makabe Syunta, Harigane Yuki, Endo Yu, Tanji Ryo, Onagi Akifumi, Matsuoka Kanako, Hoshi Seiji, Koguchi Tomoyuki, Hata Junya, Sato Yuichi, Akaihata Hidenori, Ogawa Soichiro, Kojima Yoshiyuki.
  • Organizer: International Continence Society 2021
  • Int'l Joint Research
• [Presentation] 腸内細菌叢のFirmicutes/Bacteroidetes比は前立腺腫大と関連する (2021)
  • Author(s): 竹澤健太郎, 栗林宗平, 岡田紘一, 関井洋輔, 松下慎, 福原慎一郎, 木内寛, 藤田和利, 川村憲彦, 高田晋吾, 中村昇太, 小島祥敬, 野々村祝夫.
  • Organizer: 第28回日本排尿機能学会
• [Presentation] 前立腺肥大症の細胞増殖機構解明に向けた基礎的研究 (2019)
  • Author(s): 小島祥敬
  • Organizer: 日本アンドロロジー学会第38回学術大会
  • Invited