Novel therapeutic strategies for Sjogren's syndrome targeting Toll-like receptors.

• Project/Area Number: 18H03003
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Kyushu University
• Principal Investigator: Moriyama Masafumi 九州大学, 歯学研究院, 助教 (20452774)
• Co-Investigator(Kenkyū-buntansha): 中村 誠司 九州大学, 歯学研究院, 教授 (60189040) ; 三宅 健介 東京大学, 医科学研究所, 教授 (60229812) ; 坪井 洋人 筑波大学, 医学医療系, 講師 (80580505)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: シェーグレン症候群 / Toll様受容体 / 単球/マクロファージ / 自然免疫 / モデルマウス / TLR8 / ヒトTLR8 Tg/マウスTLR8 KO マウス / Toll 様受容体 8 / TNF-α

Outline of Final Research Achievements

Recent studies suggest that Toll like receptors (TLRs) play an important role in the initiation of autoimmune diseases. In this study, we addressed to identify the disease-associated TLR related molecules in Sjogren’s syndrome (SS), and then examined both expression and function of those molecules. DNA microarray and PCR validated the up-regulation of TLR8 in SS compared with chronic sialadenitis. TLR8 is reported to recognize viral RNA and self-RNA and promote the innate immune responses via TNF-α production. Immunofluorescence double staining and flow cytometry analysis confirmed that the expression of TLR8 almost merged with that of the monocyte/macrophage marker CD68. In vitro examination of human monocyte cell line (U937) by stimulation of TLR8 agonist, concentration of TNF-α in TLR8 knock-in U937 was significantly higher than that in untreated U937 and TLR8 KO U937.. In conclusion, TLR8+ monocyte/macrophage via TNF-α secretion might be involved in the pathogenesis of SS.

Academic Significance and Societal Importance of the Research Achievements

現時点ではSSの根治的治療はいまだなく、対症療法のみである。一部の自己免疫疾患では分子標的治療薬が開発され、良好な治療成績が報告されているが、SSでは有効性が低い。これは、SSの病態には様々なサイトカインが関与していることが原因の一つとして推察される。よって本研究により、TLRといった免疫機構の上流の分子を制御することが可能となれば、SSによる腺外症状やドライマウスの改善に寄与できる。

Research Products

• [Journal Article] CD163+ M2 Macrophages Promote Fibrosis in IgG4-Related Disease Via Toll-like Receptor 7/Interleukin-1 Receptor-Associated Kinase 4/NF-κB Signaling (2022)
  • Author(s): Chinju Akira、Moriyama Masafumi、Kakizoe‐Ishiguro Noriko、Chen Hu、Miyahara Yuka、Haque A. S. M. Rafiul、Furusho Katsuhiro、Sakamoto Mizuki、Kai Kazuki、Kibe Kotono、Hatakeyama‐Furukawa Sachiko、Ito‐Ohta Miho、Maehara Takashi、Nakamura Seiji
  • Journal Title: Arthritis & Rheumatology Volume: in press Issue: 5 Pages: 1-10
  • DOI: 10.1002/art.42043
  • Peer Reviewed / Open Access
• [Journal Article] Orchestration of Immune Cells Contributes to Fibrosis in IgG4-Related Disease (2022)
  • Author(s): Kaneko Naoki、Moriyama Masafumi、Maehara Takashi、Chen Hu、Miyahara Yuka、Nakamura Seiji
  • Journal Title: Immuno Volume: 2 Issue: 1 Pages: 170-184
  • DOI: 10.3390/immuno2010013
  • Peer Reviewed / Open Access
• [Journal Article] Dental pulp-derived stem cell-conditioned media attenuates secondary Sj?gren's syndrome via suppression of inflammatory cytokines in the submandibular glands (2021)
  • Author(s): Ogata Kenichi、Matsumura-Kawashima Mayu、Moriyama Masafumi、Kawado Tatsuya、Nakamura Seiji
  • Journal Title: Regenerative Therapy Volume: 16 Pages: 73-80
  • DOI: 10.1016/j.reth.2021.01.006
  • Peer Reviewed / Open Access
• [Journal Article] Secreted factors from dental pulp stem cells improve sjogre’s syndrome via regulatory T cell-mediated immunosuppression (2021)
  • Author(s): Matsumura-Kawashima et al.
  • Journal Title: Stem Cell Research & Therapy Volume: 2021 Issue: 1 Pages: 1-16
  • DOI: 10.1186/s13287-021-02236-6
  • Peer Reviewed / Open Access
• [Journal Article] Investigation of IgG4‐positive cells in idiopathic multicentric Castleman disease and validation of the 2020 exclusion criteria for IgG4‐related disease (2021)
  • Author(s): Nishikori Asami、Nishimura Midori Filiz、Nishimura Yoshito、Notohara Kenji、Satou Akira、Moriyama Masafumi、Nakamura Seiji、Sato Yasuharu
  • Journal Title: Pathology International Volume: 72 Issue: 1 Pages: 43-52
  • DOI: 10.1111/pin.13185
  • Peer Reviewed / Open Access
• [Journal Article] Oral Squamous Cell Carcinoma Contributes to Differentiation of Monocyte-Derived Tumor-Associated Macrophages via PAI-1 and IL-8 Production (2021)
  • Author(s): Kai Kazuki、Moriyama Masafumi、Haque A. S. M. Rafiul、Hattori Taichi、Chinju Akira、Hu Chen、Kubota Keigo、Miyahara Yuka、Kakizoe-Ishiguro Noriko、Kawano Shintaro、Nakamura Seiji
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 17 Pages: 9475-9475
  • DOI: 10.3390/ijms22179475
  • Peer Reviewed / Open Access
• [Journal Article] CD4+ and CD8+ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG4-related disease (2021)
  • Author(s): Perugino Cory A., Moriyama Masafumi（28名中24番目）, et al.
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: 147 Issue: 1 Pages: 368-382
  • DOI: 10.1016/j.jaci.2020.05.022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] RORγt antagonist improves Sj?gren's syndrome‐like sialadenitis through downregulation of CD25 (2020)
  • Author(s): Ono Yuko、Tsuboi Hiroto、Moriyama Masafumi、Asashima Hiromitsu、Kudo Hanae、Takahashi Hiroyuki、Honda Fumika、Abe Saori、Kondo Yuya、Takahashi Satoru、Matsumoto Isao、Nakamura Seiji、Sumida Takayuki
  • Journal Title: Oral Diseases Volume: - Issue: 4 Pages: 766-777
  • DOI: 10.1111/odi.13255
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activated M2 macrophage contributes to the pathogenesis of IgG4-related disease via TLR7/IL-33 signalin. (2019)
  • Author(s): Ishiguro N, Moriyama M, Furusho K, Furukawa S, Shibata T, Murakami Y, Chinju A, Haque ASMR, Gion Y, Ohta M, Maehara T, Tanaka A, Yamauchi M, Sakamoto M, Mochizuki K, Ono Y, Hayashida JN, Sato Y, Kiyoshima T, Yamamoto H, Miyake K, Nakamura S
  • Journal Title: Arthritis Rheumatol. Volume: Jan;72(1) Issue: 1 Pages: 166-178
  • DOI: 10.1002/art.41052
  • Peer Reviewed / Open Access
• [Journal Article] 2.Tissue-infiltrating immune cells contribute to understanding the pathogenesis of Kimura disease: A case report (2019)
  • Author(s): Maehara T, Munemura R, Shimizu M, Kakizoe N, Kaneko N, Murakami Y, Moriyama M, Kiyoshima T, Kawano S, Nakamura S.
  • Journal Title: Medicine Volume: in press Issue: 50 Pages: e18300-e18300
  • DOI: 10.1097/md.0000000000018300
  • Peer Reviewed / Open Access
• [Journal Article] The diagnostic utility of submandibular gland sonography and labial salivary gland biopsy in IgG4-related dacryoadenitis and sialadenitis: Its potential application to the diagnostic criteria (2019)
  • Author(s): Sakamoto Mizuki、Moriyama Masafumi、Shimizu Mayumi、Chinju Akira、Mochizuki Keita、Munemura Ryusuke、Ohyama Keiko、Maehara Takashi、Ogata Kenichi、Ohta Miho、Yamauchi Masaki、Ishiguro Noriko、Matsumura Mayu、Ohyama Yukiko、Kiyoshima Tamotsu、Nakamura Seiji
  • Journal Title: Modern Rheumatology Volume: - Issue: 2 Pages: 1-6
  • DOI: 10.1080/14397595.2019.1576271
  • Peer Reviewed / Open Access
• [Journal Article] Upregulation and pathogenic roles of CCL18-CCR8 axis in IgG4-related disease (2019)
  • Author(s): Tsuboi Hiroto、Iizuka-Koga Mana、Asashima Hiromitsu、Takahashi Hiroyuki、Kudo Hanae、Ono Yuko、Honda Fumika、Iizuka Akira、Segawa Seiji、Abe Saori、Yagishita Mizuki、Yokosawa Masahiro、Kondo Yuya、Moriyama Masafumi、Matsumoto Isao、Nakamura Seiji、Sumida Takayuki
  • Journal Title: Modern Rheumatology Volume: - Issue: 4 Pages: 1-9
  • DOI: 10.1080/14397595.2019.1632061
  • Peer Reviewed / Open Access
• [Journal Article] Cytidine deaminase enables Toll-like receptor 8 activation by cytidine or its analogs. (2019)
  • Author(s): Furusho K, Shibata T, Sato R, Fukui R, Motoi Y, Zhang Y, Saitoh SI, Ichinohe T, Moriyama M, Nakamura S, Miyake, K.
  • Journal Title: International immunology. Volume: 31 Issue: 3 Pages: 167-173
  • DOI: 10.1093/intimm/dxy075
  • Peer Reviewed / Open Access
• [Journal Article] Pathogenesis of IgG4-related disease: a critical review (2018)
  • Author(s): Maehara Takashi、Moriyama Masafumi、Nakamura Seiji
  • Journal Title: Odontology Volume: 107 Issue: 2 Pages: 127-132
  • DOI: 10.1007/s10266-018-0377-y
  • Peer Reviewed / Open Access
• [Journal Article] Clinical practice guideline for Sj?gren’s syndrome 2017 (2018)
  • Author(s): Sumida Takayuki、Azuma Naoto、Moriyama Masafumi、Takahashi Hiroyuki、Asashima Hiromitsu、Honda Fumika、Abe Saori、Ono Yuko、Hirota Tomoya、Hirata Shintaro、Tanaka Yoshiya、Shimizu Toshimasa、Nakamura Hideki、Kawakami Atsushi、Sano Hajime、Ogawa Yoko、Tsubota Kazuo、Ryo Koufuchi、Saito Ichiro、Tsuboi Hiroto
  • Journal Title: Modern Rheumatology Volume: 28 Issue: 3 Pages: 383-408
  • DOI: 10.1080/14397595.2018.1438093
  • Peer Reviewed / Open Access
• [Presentation] TLR8+CD68+monocyte/macrophage contribute to the pathogenesis of Sj0gren’s syndrome via TNF-α secretion. (2019)
  • Author(s): Mizuki Sakamoto, Masafumi Moriyama, Noriko Ishiguro, and Seiji Nakamura
  • Organizer: KOB International Symposium 2019
  • Int'l Joint Research / Invited
• [Presentation] CD68+ monocyte/macrophage contributes to the pathogenesis of Sjogren’s syndrome via TLR8/TNF-α signaling (2019)
  • Author(s): Mizuki Sakamoto, Masafumi Moriyama, Noriko Ishiguro, and Seiji Nakamura
  • Organizer: The 60th Korean Association of Oral & Maxillofacial Surgeons
  • Int'l Joint Research
• [Presentation] Involvement of Toll like receptor 8 in the pathogenesis of Sjogren’s syndrome (2018)
  • Author(s): Mizuki SAKAMOTO, Masafumi MORIYAMA, Keiko OYAMA, Akihiko TANAKA, Takashi MAEHARA, Kenichi OGATA, Sachiko FURUKAWA, Miho OHTA, Masaki YAMAUCHI, Noriko ISHIGURO, Haque A. S. M. RAFIUL, Akira CHINJU, Keita MOCHIZUKI, Mayu MATSUMURA, Ryusuke MUNEMURA, Jun-Nosuke HAYASHIDA, and Seiji NAKAMURA
  • Organizer: The 59th Annual Congress of Korean Association of Oral and Maxillofacial Surgeons
  • Int'l Joint Research
• [Presentation] TLR8+CD68+ monocyte/macrophage contributes to the pathogenesis of Sjogren’s syndrome. (2018)
  • Author(s): Mizuki SAKAMOTO, Masafumi MORIYAMA, Keiko OYAMA, Akihiko TANAKA, Takashi MAEHARA, Kenichi OGATA, Sachiko FURUKAWA, Miho OHTA, Masaki YAMAUCHI, Noriko ISHIGURO, Haque A. S. M. RAFIUL, Akira CHINJU, Keita MOCHIZUKI, Mayu MATSUMURA, Ryusuke MUNEMURA, Jun-Nosuke HAYASHIDA, and Seiji NAKAMURA
  • Organizer: 第 66 回 国際歯科研究学会日本部会
• [Book] シェーグレン症候群の診断と治療マニュアル 改訂第3版 (2018)
  • Author(s): 森山 雅文、中村 誠司
  • Total Pages: 268
  • Publisher: 診断と治療社