The role of macrophages in the pathogeneses of Sjogren's syndrome

• Project/Area Number: 16H05511
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathobiological dentistry/Dental radiology
• Research Institution: The University of Tokushima
• Principal Investigator: ARAKAKI Rieko 徳島大学, 大学院医歯薬学研究部(歯学域), 准教授 (00193061)
• Co-Investigator(Kenkyū-buntansha): 山田 安希子 徳島大学, 大学院医歯薬学研究部(歯学域), 助教 (70452646)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2018: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2016: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
• Keywords: 自己免疫疾患 / シェーグレン症候群 / マクロファージ / 組織常在型マクロファージ / ケモカイン / ccl22 / 唾液腺常在マクロファージ / 唾液腺

Outline of Final Research Achievements

Macrophages are critical regulators of immune response and serve as a link between innate and acquired immunity. Using a murine model for Sjogren’s syndrome (SS), we investigated the role of tissue-resident macrophages in the onset and development of autoimmunity. Two unique populations of CD11b high and CD11blow resident macrophages were observed in the target tissue of the SS model. PCR array analysis of chemokines revealed effective production of CCL22 by the CD11b high macrophages. CCL22 upregulated the migratory activity of CD4+T cells. Moreover, administration of anti-CCL22 antibody suppressed autoimmune lesions in the SS model. In conclusion, CCL22-producing tissue-resident macrophages controls autoimmune lesions via autoreactive T cells in the SS model. These results suggest that specific chemokines and their receptors may serve as novel therapeutic targets for SS.

Academic Significance and Societal Importance of the Research Achievements

自然免疫においてマクロファージは代表的な貪食細胞であるが、近年、マクロファージの活性化状態には多様性があり、炎症誘導性のM1マクロファージや組織修復・免疫抑制を誘導して炎症を終結させるM2マクロファージ等が存在することが明らかになってきた。しかし自己免疫疾患におけるマクロファージの役割を明らかにした報告は少ない。炎症初期から後期まで多種多様に関与するマクロファージの動態を明らかにすることは、自己免疫疾患発症の機序解明に大いに役立つはずである。また本研究は、SSのみならず他の自己免疫疾患や慢性炎症に起因する疾患に応用できると考えられ、多くの慢性炎症疾患の治療法開発に繋がることを期待している。

Research Products

• [Journal Article] IL-10 and CXCL2 in trigeminal ganglia in neuropathic pain. (2019)
  • Author(s): Iwasa T, Afroz S, Inoue M, Arakaki R, Oshima M, Raju R, Waskitho A, Inoue M, Baba O, Matsuka Y.
  • Journal Title: Neurosci Lett. Volume: 703 Pages: 132-138
  • DOI: 10.1016/j.neulet.2019.03.031
  • Peer Reviewed / Open Access
• [Journal Article] CGRP Induces Differential Regulation of Cytokines from Satellite Glial Cells in Trigeminal Ganglia and Orofacial Nociception. (2019)
  • Author(s): Afroz S, Arakaki R, Iwasa T, Oshima M, Hosoki M, Inoue M, Baba O, Okayama Y, Matsuka Y.
  • Journal Title: Int J Mol Sci. Volume: 20 Issue: 3 Pages: 1-20
  • DOI: 10.3390/ijms20030711
  • Peer Reviewed / Open Access
• [Journal Article] CCL22-Producing Resident Macrophages Enhance T Cell Response in Sjogren's Syndrome. (2018)
  • Author(s): Ushio A, Arakaki R, Otsuka K, Yamada A, Tsunematsu T, Kudo Y, Aota K, Azuma M, Ishimaru N.
  • Journal Title: Front Immunol. Volume: 8 Pages: 1-15
  • Peer Reviewed / Open Access
• [Journal Article] Long-term polarization of alveolar macrophages to a profibrotic phenotype after inhalation exposure to multi-wall carbon nanotubes. (2018)
  • Author(s): Otsuka K, Yamada K, Taquahashi Y, Arakaki R, Ushio A, Saito M, Yamada A, Tsunematsu T, Kudo Y, Kanno J, Ishimaru N.
  • Journal Title: PLoS One. Volume: 13(10) Issue: 10 Pages: 1-18
  • DOI: 10.1371/journal.pone.0205702
  • Peer Reviewed / Open Access
• [Journal Article] Role of Fas and RANKL signaling in peripheral immune tolerance (2017)
  • Author(s): Izawa T., Arakaki R., Ishimaru N.
  • Journal Title: Journal of Clinical & Cellular Immunology Volume: 8 Issue: 04 Pages: 512-512
  • DOI: 10.4172/2155-9899.1000512
  • Peer Reviewed / Open Access
• [Journal Article] Pathological Analysis of Ocular Lesions in a Murine Model of Sjögren’s Syndrome (2017)
  • Author(s): Ushio A, Arakaki R, Eguchi H, Hotta F, Yamada A, Kudo Y, Ishimaru N
  • Journal Title: Int J Mol Sci. Volume: 18 Issue: 6 Pages: 1209
  • DOI: 10.3390/ijms18061209
  • URL: https://tokushima-u.repo.nii.ac.jp/records/2004888
  • Peer Reviewed / Open Access
• [Journal Article] Establishment and characterization of a clear cell odontogenic carcinoma cell line with EWSR1-ATF1 fusion gene. (2017)
  • Author(s): Kujiraoka S, Tsunematsu T, Sato Y, Yoshida M, Tohyama R, Tanaka M, Kobayashi Y, Kondo T, Ushio A, Otsuka K, Kurosawa M, Saito M. Yamada A, Arakaki R, Nagai H, Nikai H, Takeuchi K, Nagao T, Miyamoto Y, Ishimaru N, Kudo Y.
  • Journal Title: Oral Oncol. Volume: 69 Pages: 46-55
  • DOI: 10.1016/j.oraloncology.2017.04.003
  • Peer Reviewed / Open Access
• [Journal Article] Dual role of Fas/FasL-mediated signal in peripheral immune tolerance. (2017)
  • Author(s): Yamada A, Arakaki R, Saito M, Kudo Y, Ishimaru N.
  • Journal Title: Front in Immunol. Volume: 8 Pages: 403-403
  • DOI: 10.3389/fimmu.2017.00403
  • NAID: 120006374401
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] NF-κB2 Controls the Migratory Activity of Memory T Cells by Regulating Expression of CXCR4 in a Mouse Model of Sjogren's Syndrome. (2017)
  • Author(s): Kurosawa M, Arakaki R, Yamada A, Tsunematsu T, Kudo Y, Sprent J, Ishimaru N.
  • Journal Title: Arthritis Rheumatol. Volume: 69 Issue: 11 Pages: 2193-2202
  • DOI: 10.1002/art.40230
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Unique Phenotypes and Functions of Follicular Helper T Cell and Regulatory T Cell in Sjogren's Syndrome. (2017)
  • Author(s): Saito M, Otsuka K, Ushio A, Yamada A, Arakaki R, Kudo Y, Ishimaru N.
  • Journal Title: Current Rheumatology Reviews Volume: 13 Issue: 3 Pages: 239-245
  • DOI: 10.2174/1573397113666170125122858
  • Peer Reviewed / Open Access
• [Journal Article] Acceleration of tumor growth due to dysfunction in Ma macrophages and enhanced angiogenesis in an animal model of autoimmune disease. (2016)
  • Author(s): Kondo T, Tsunematsu T, Yamada A, Arakaki R, Saito M, Otsuka K, Kujiraoka S, Ushio A, Kurosawa M, Kudo Y, Ishimaru N.
  • Journal Title: Lab Invest Volume: 96 Issue: 4 Pages: 468-480
  • DOI: 10.1038/labinvest.2015.166
  • Peer Reviewed / Open Access
• [Journal Article] Human odontogenic epithelial cells derived from epithelial rests of Malassez possess stem cell properties. (2016)
  • Author(s): Tsunematsu T, Fujiwara N, Yoshida M, Takayama Y, Kujiraoka S, Qi G, Kitagawa M, Kondo T, Yamada A, Arakaki R, Miyauchi M, Ogawa I, Abiko Y, Nikawa H, Murakami S, Takata T, Ishimaru N, Kudo Y.
  • Journal Title: Lab Invest. Volume: 96(10) Issue: 10 Pages: 1063-1075
  • DOI: 10.1038/labinvest.2016.85
  • NAID: 120006718349
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Nuclear Receptor AhR Controls Bone Homeostasis by Regulating Osteoclast Differentiation via the RANK/c-Fos Signaling Axis. (2016)
  • Author(s): Izawa T, Arakaki R, Mori H, Tsunematsu T, Kudo Y, Tanaka E, Ishimaru N.
  • Journal Title: Journal of Immunology Volume: 197 Issue: 12 Pages: 4639-4650
  • DOI: 10.4049/jimmunol.1600822
  • Peer Reviewed / Open Access
• [Presentation] CCL22-Producing Resident Macrophages Enhances InflaMMation in Salivary Glands of Sjogren's Syndorome. (2018)
  • Author(s): Aya Ushio, Rieko Arakaki, Kunihiro Ohtsuka, Yasusei Kudo and Naozumi Ishimaru
  • Organizer: 11th International Congress of Autoimmunity
  • Int'l Joint Research
• [Presentation] NF-kB2 Controls the Migratory of Memory T cells to the Target Tissues in a Mouse Model of Sjogren's Syndorome by Regulating Expression of CXCR4 (2018)
  • Author(s): Rieko Arakaki, Aya Ushio, Kunihiro Ohtsuka, Yasusei Kudo and Naozumi Ishimaru
  • Organizer: 11th International Congress of Autoimmunity
  • Int'l Joint Research
• [Presentation] CCL22-producing macrophages promote T cell autoimmunity in the target organ of Sjogren's syndorome. (2018)
  • Author(s): Aya Ushio, Rieko Arakaki, Kunihiro Ohtsuka, Akiko Yamada, Yasusei Kudo and Naozumi Ishimaru
  • Organizer: The 47th Annual meeting of the Japanese society for immunology
• [Presentation] CCL22産生唾液腺マクロファージはシェーグレン症候群の病態に関与する, (2018)
  • Author(s): 牛尾 綾, 新垣 理恵子, 大塚 邦紘, 工藤 保誠, 石丸 直澄
  • Organizer: 第28回日本シェーグレン症候群学会
• [Presentation] 全身吸入暴露による多層化カーボンナノチューブの肺胞マクロファージへの影響 (2018)
  • Author(s): 新垣 理恵子, 牛尾 綾, 大塚 邦紘, 工藤 保誠, 石丸 直澄
  • Organizer: 第107回日本病理学会総
• [Presentation] シェーグレン症候群モデルマウス唾液腺におけるIL-33の発現とその役割, (2018)
  • Author(s): 中山 慎一朗, 新垣 理恵子, 牛尾 綾, 大塚 邦紘, 常松 貴明, 工藤 保誠, 石丸 直澄
  • Organizer: 第107回日本病理学会総会
• [Presentation] The role of the cleaved form IL-33 in pathogenesis of Sjogren’s syndrome (SS) (2018)
  • Author(s): Rieko Arakaki, Shinichiro Nakayama, Aya Ushio, Kunihiro Otsuka, Satoshi Kisoda, Takaaki Tsunematsu, Akiko Yamada,Yasusei Kudo, Naozumi Ishimaru
  • Organizer: The 47th Annual meeting of the Japanese society for immunology
• [Presentation] Crosstalk between cytokine RANKL and AhR signaling in osteoclasts controls bone homeostasis (2018)
  • Author(s): Takashi Izawa, Rieko Arakaki, Eiji Tanaka and Naozumi Ishimaru
  • Organizer: Gordon Research Conference; "Bones and Teeth" From Skeletal and Dental Stem Cells to Rare Bone Disease and Integrative Physiology
  • Int'l Joint Research
• [Presentation] Crosstalk between cytokine RANKL and AhR signaling in osteoclasts controls bone homeostasis (2017)
  • Author(s): Takashi Izawa, Rieko Arakaki, Eiji Tanaka and Naozumi Ishimaru
  • Organizer: The 46th Annual Meeting of the Japanese Society for Immunology
• [Presentation] シェーグレン症候群モデルマウスの唾液腺マクロファージと病態への関与, (2017)
  • Author(s): 牛尾 綾, 新垣 理恵子, 山田 安希子, 大塚 邦紘, 黒澤 実愛, 工藤 保誠, 石丸 直澄
  • Organizer: 第16回四国免疫フォーラム
• [Presentation] Chronic influence of Multi-walled carbon nanotubes (MWCNT) on immune system (2017)
  • Author(s): 新垣 理恵子, 山田 耕一, 齋藤 雅子, 大塚 邦紘, 山田 安希子, 常松 貴明, 工藤 保誠, 菅野 純, 石丸 直澄
  • Organizer: 第106回日本病理学会総会,
• [Presentation] シェーグレン症候群の唾液腺におけるマクロファージサブセットと病態への関与, (2017)
  • Author(s): 牛尾 綾, 新垣 理恵子, 山田 安希子, 大塚 邦紘, 鯨岡 聡子, 常松 貴明, 工藤 保誠, 石丸 直澄
  • Organizer: 第106回日本病理学会総会
• [Presentation] シェーグレン症候群モデルマウスにおける濾胞ヘルパーT細胞の解析, (2017)
  • Author(s): 大塚 邦紘, 山田 安希子, 齋藤 雅子, 牛尾 綾, 黒澤 実愛, 鯨岡 聡子, 常松 貴明, 工藤 保誠, 新垣 理恵子, 石丸 直澄
  • Organizer: 第106回日本病理学会総会
• [Presentation] Analysis of follicular helper T cells in a mouse model for Sjogren's syndrome (2017)
  • Author(s): 大塚邦紘、山田安希子、黒澤実愛、牛尾 綾、新垣理恵子、工藤保誠、石丸直澄
  • Organizer: The 46th Annual Meeting of the Japanese Society for Immunology
• [Presentation] CCL22-producing resident macrophages enhances autoimmune lesions in a mouse model of Sjogren's syndrome. (2017)
  • Author(s): 牛尾 綾、新垣理恵子、山田安希子、大塚邦紘、工藤保誠、石丸直澄
  • Organizer: The 46th Annual Meeting of the Japanese Society for Immunology
• [Presentation] Analysis of macrophages in the pathogenesis of a murine model for Sjogren's syndrome (2016)
  • Author(s): Ushio Aya, Arakaki RIeko, Saito Masako, Yamada Akiko, Otsuka Kunihiro, Kurosawa Mie Kujiraoka Satoko Kudo Yasusei Ishimaru Naozumi
  • Organizer: 第45回日本免疫学会総会
  • Place of Presentation: 沖縄コンベンションセンター （沖縄県・宜野湾市 ）
  • Year and Date: 2016-12-05
• [Presentation] NF-kappaB regulates migratory function of effector memory T cells in autoimmunity (2016)
  • Author(s): Kurasawa Mie, Yamada Akiko, Arakaki Rieko, Tsunematu Takaaki, Kudo Yasusei, Saitou Masako, Ishimaru Naozumi
  • Organizer: 第45回日本免疫学会総会
  • Place of Presentation: 沖縄コンベンションセンター （沖縄県・宜野湾市 ）
  • Year and Date: 2016-12-05
• [Presentation] Immunological and toxicological effect of multi-wall carbon nanotubes by whole body inhalation exposure in B6 mice (2016)
  • Author(s): Arakaki rieko, Yamada Akiko, Ushio Aya, Kurosawa Mie, Otsuka Kunihiro, Saito Masako, Tsunematsu Takaaki, Kudo Yasusei, Ishimaru naozumi
  • Organizer: 第45回日本免疫学会総会
  • Place of Presentation: 沖縄コンベンションセンター（沖縄県・宜野湾市 ）
  • Year and Date: 2016-12-05
• [Presentation] シェーグレン症候群の病態形成におけるマクロファージの役割 (2016)
  • Author(s): 牛尾 綾、新垣理恵子、山田安希子、石丸直澄
  • Organizer: 第25回日本シェーグレン症候群学会学術集会
  • Place of Presentation: 京王プラザホテル（東京都・新宿区）
  • Year and Date: 2016-09-08
• [Presentation] Abnormal germinal center(GC)reaction in autoimmunity. (2016)
  • Author(s): Masako Saito, Kunihiro Otsuka Aya Ushio, Mie Kurosawa, Akiko Yamada, Yasusei Kudo, Rieko Arakaki and Naozumi Ishimaru
  • Organizer: International congress of Immunology 2016
  • Place of Presentation: Melbourne (Australia)
  • Year and Date: 2016-08-21
  • Int'l Joint Research
• [Presentation] 全身吸入暴露による多層化カーボンナノチューブの免疫システムへの影響, (2016)
  • Author(s): 新垣 理恵子, 常松 貴明, 山田 安希子, 齋藤 雅子, 工藤 保誠, 石丸 直澄
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2016-05-12
• [Presentation] シェーグレン症候群モデルマウスの病態形成におけるマクロファージの役割 (2016)
  • Author(s): 牛尾 綾、新垣理恵子、山田安希子、工藤保誠、石丸直澄
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2016-05-12