Analysis of the mechanism by which lipid-recognizing paired immnue receptors regulate inflammation

• Project/Area Number: 17H04217
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Juntendo University
• Principal Investigator: Kitaura Jiro 順天堂大学, 医学(系)研究科(研究院), 先任准教授 (30282651)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2017: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: 炎症 / アレルギー / ペア型免疫受容体 / 脂質 / アレルギー・喘息 / 免疫学 / シグナル伝達

Outline of Final Research Achievements

We elucidate the mechanisms underlying lipid-recognizing paired immune receptors regulate inflammation. An inhibitory receptor LMIR3 inhibits IgE-dependent and independent activating signals by binding to ceramide, thereby suppressing IgE-dependent anaphylaxis and food allergy and IgE-independent inflammation such as pseudo-allergy. On the other hand, we provide evidence that activating receptors LMIR6 and LMIR7 promote inflammation by binding to specific lipids similar to ceramides. In addition, we demonstrate that the differential recognition of lipid ligands by mouse versus human LMIR3 depends on the difference of a single amino acid in their extracellular domains.

Academic Significance and Societal Importance of the Research Achievements

ペア型免疫受容体は免疫細胞の活性化を促進あるいは抑制して免疫応答を調整する。本研究により、抑制型受容体LMIR3が特定の脂質を認識してアレルギーや炎症を抑えること、また、対をなす活性化型受容体は類似の脂質を認識して炎症を促進することが示された。従って、LMIR分子を標的とする特定の脂質は炎症を抑える薬剤として利用可能である。このように、本研究の意義は炎症性疾患に対する新規治療法開発の分子基盤が形成された点にある。

Research Products

• [Int'l Joint Research] University Hospital Erlangen/Medical Faculty Carl Gustav Carus(ドイツ)
• [Int'l Joint Research] University Hospital Erlangen/Technische Universität Dresden(Germany)
• [Journal Article] Differential Lipid Recognition by Mouse versus Human CD300f, Inhibiting Passive Cutaneous Anaphylaxis, Depends on a Single Amino Acid Substitution in its Immunoglobulin-Like Domain (2020)
  • Author(s): Izawa K、Kaitani A、Ando Tomoaki、Maehara A、Nagamine M、Yamada H、Ando T、Ide T、Matsuzawa M、Okamoto Y、Yin E、Fukase S、Wang H、Kamei A、Uchida S、Maeda K、Nakano N、Uchida K、Tamura N、Ikeda K、Ebihara N、Shimizu T、Voehringer D、Roers A、Ogawa H、Okumura K、Kitaura J
  • Journal Title: Journal of Investigative Dermatology Volume: 140 Issue: 3 Pages: 710-713
  • DOI: 10.1016/j.jid.2019.08.439
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD300f is a potential therapeutic target for the treatment of food allergy (2019)
  • Author(s): Uchida Shino、Izawa Kumi、Ando Tomoaki、Yamada Hiromichi、Uchida Koichiro、Negishi Naoko、Kaitani Ayako、Maehara Akie、Nagamine Masakazu、Kamei Anna、Takamori Ayako、Maeda Keiko、Nakano Nobuhiro、Shimizu Toshiaki、Ogawa Hideoki、Okumura Ko、Nagahara Akihito、Watanabe Sumio、Kitaura Jiro
  • Journal Title: Allergy Volume: 75 Issue: 2 Pages: 471-474
  • DOI: 10.1111/all.14034
  • NAID: 40022209298
  • Peer Reviewed / Open Access
• [Journal Article] Receptor-destroying enzyme (RDE) from Vibrio cholerae modulates IgE activity and reduces the initiation of anaphylaxis (2019)
  • Author(s): Yamazaki Tatsuya、Inui Masanori、Hiemori Keiko、Tomono Susumu、Itoh Makoto、Ichimonji Isao、Nakashima Akina、Takagi Hidekazu、Biswas Mrityunjoy、Izawa Kumi、Kitaura Jiro、Imai Teruko、Sugiura Nobuo、Tateno Hiroaki、Akashi-Takamura Sachiko
  • Journal Title: Journal of Biological Chemistry Volume: 294 Issue: 17 Pages: 6659-6669
  • DOI: 10.1074/jbc.ra118.006375
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] NUP98-HBO1-fusion generates phenotypically and genetically relevant chronic myelomonocytic leukemia pathogenesis (2019)
  • Author(s): Hayashi Yoshihiro、Harada Yuka、Kagiyama Yuki、Nishikawa Sayuri、Ding Ye、Imagawa Jun、Shingai Naoki、Kato Naoko、Kitaura Jiro、Hokaiwado Shintaro、Maemoto Yuki、Ito Akihiro、Matsui Hirotaka、Kitabayashi Issay、Iwama Atsushi、Komatsu Norio、Kitamura Toshio、Harada Hironori
  • Journal Title: Blood Advances Volume: 3 Issue: 7 Pages: 1047-1060
  • DOI: 10.1182/bloodadvances.2018025007
  • Peer Reviewed / Open Access
• [Journal Article] Identification of inhibitory mechanisms in pseudo-allergy involving Mrgprb2/MRGPRX2-mediated mast cell activation (2019)
  • Author(s): Takamori A, Ozawa K, Kaitani A, Ando T, Okamoto Y, Maehara A, Tanabe A, Nagamine M, Yamada H, Uchida S, Uchida K, Isobe M, Hatayama T, Watanabe D, Ando T, Ide T, Matsuzawa M, Maeda K, Nakano N, Tamura N, Ikeda K, Ebihara N, Shimizu T, Ogawa H, Okumura K, Kitaura J
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: 143 Issue: 3 Pages: 1231-1235
  • DOI: 10.1016/j.jaci.2018.10.034
  • Peer Reviewed / Open Access
• [Journal Article] The phytosphingosine-CD300b interaction promotes zymosan-induced, nitric oxide?dependent neutrophil recruitment (2019)
  • Author(s): Takahashi Mariko、Izawa Kumi、Urai Makoto、Yamanishi Yoshinori、Maehara Akie、Isobe Masamichi、Matsukawa Toshihiro、Kaitani Ayako、Takamori Ayako、Uchida Shino、Yamada Hiromichi、Nagamine Masakazu、Ando Tomoaki、Shimizu Toshiaki、Ogawa Hideoki、Okumura Ko、Kinjo Yuki、Kitamura Toshio、Kitaura Jiro
  • Journal Title: Science Signaling Volume: 12 Issue: 564 Pages: 564-564
  • DOI: 10.1126/scisignal.aar5514
  • Peer Reviewed / Open Access
• [Journal Article] IL-31 is crucial for induction of pruritus, but not inflammation, in contact hypersensitivity. (2018)
  • Author(s): Takamori A, Nambu A, Sato K, Yamaguchi S, Matsuda K, Numata T, Sugawara T, Yoshizaki T, Arae K, Morita H, Matsumoto K, Sudo K, Okumura K, Kitaura J, Matsuda H, Nakae S
  • Journal Title: Sci Rep. Volume: 8 Pages: 6639-6639
  • Peer Reviewed / Open Access
• [Journal Article] Leukocyte mono-immunoglobulin-like receptor 8 (LMIR8)/CLM-6 is an FcRγ-coupled receptor selectively expressed in mouse tissue plasmacytoid dendritic cells (2018)
  • Author(s): Kaitani A, Izawa K, Maehara A, Isobe M, Takamori A, Matsukawa T, Takahashi M, Yamanishi Y, Oki T, Yamada H, Nagamine M, Uchida S, Uchida K, Ando T, Maeda K, Nakano N, Shimizu T, Takai T, Ogawa H, Okumura K, Kitamura T, Kitaura J
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 8259-8259
  • DOI: 10.1038/s41598-018-25646-8
  • Peer Reviewed / Open Access
• [Journal Article] The Fab fragment of anti-IgE Cε2 domain prevents allergic reactions through interacting with IgE-FcεRIα complex on rat mast cells. (2018)
  • Author(s): Hirano T, Koyanagi A, Kotoshiba K, Shinkai Y, Kasai M, Ando T, Kaitani A, Okumura K, Kitaura J
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 14237-14237
  • DOI: 10.1038/s41598-018-32200-z
  • Peer Reviewed / Open Access
• [Journal Article] Mouse LIMR3/CD300f is a negative regulator of the antimicrobial activity of neutrophils (2018)
  • Author(s): Ueno Keigo、Urai Makoto、Izawa Kumi、Otani Yoshiko、Yanagihara Nao、Kataoka Michiyo、Takatsuka Shogo、Abe Masahiro、Hasegawa Hideki、Shimizu Kiminori、Kitamura Toshio、Kitaura Jiro、Miyazaki Yoshitsugu、Kinjo Yuki
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 17406-17406
  • DOI: 10.1038/s41598-018-35699-4
  • Peer Reviewed / Open Access
• [Journal Article] CD155-Transducing Signaling through TIGIT Plays an Important Role in Transmission of Tolerant State and Suppression Capacity (2018)
  • Author(s): Negishi Naoko、Sato Takehito、Yamashita-Kanemaru Yumi、Shibuya Kazuko、Uchida Koichiro、Kametani Yoshie、Yagita Hideo、Kitaura Jiro、Okumura Ko、Habu Sonoko
  • Journal Title: ImmunoHorizons Volume: 2 Issue: 10 Pages: 338-348
  • DOI: 10.4049/immunohorizons.1800033
  • Peer Reviewed / Open Access
• [Journal Article] Role of the ceramide-CD300f interaction in gram-negative bacterial skin infections. (2018)
  • Author(s): Maehara A, Kaitani A, Izawa K, Shiba E, Nagamine M, Takamori A, Isobe M, Uchida S, Uchida K, Ando T, Keiko M, Nakano N, Voehringer D, Roers A, Shimizu T, Ogawa H, Okumura K, Kitamura T, Kitaura J.
  • Journal Title: J Invest Dermatol. Volume: 138 Issue: 5 Pages: 1221-1224
  • DOI: 10.1016/j.jid.2017.11.025
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The CD300e molecule in mice is an immune-activating receptor. (2018)
  • Author(s): Isobe M, Izawa K, Sugiuchi M, Sakanishi T, Kaitani A, Takamori A, Maehara A, Matsukawa T, Takahashi M, Yamanishi Y, Oki T, Uchida S, Uchida K, Ando T, Maeda K, Nakano N, Yagita H, Takai T, Ogawa H, Okumura K, Kitamura T, Kitaura J.
  • Journal Title: J Biol Chem. Volume: 293 Issue: 10 Pages: 3793-3805
  • DOI: 10.1074/jbc.ra117.000696
  • Peer Reviewed / Open Access
• [Journal Article] Disrupting ceramide-CD300f interaction prevents septic peritonitis by stimulating neutrophil recruitment. (2017)
  • Author(s): Izawa K, Maehara A, Isobe M, Yasuda Y, Urai M, Hoshino Y, Ueno K, Matsukawa T, Takahashi M, Kaitani A, Shiba E, Takamori A, Uchida S, Uchida K, Maeda K, Nakano N, Yamanishi Y, Oki T, Voehringer D, Roers A, Nakae S, Ishikawa J, Kinjo Y, Shimizu T, Ogawa H, Okumura K, Kitamura T, Kitaura J
  • Journal Title: Sci Rep. Volume: 7(1) Issue: 1 Pages: 4298-4298
  • DOI: 10.1038/s41598-017-04647-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High expression of ABCG2 induced by EZH2 disruption has pivotal roles in MDS pathogenesis (2017)
  • Author(s): Kawabata K C、Hayashi Y、Inoue D、Meguro H、Sakurai H、Fukuyama T、Tanaka Y、Asada S、Fukushima T、Nagase R、Takeda R、Harada Y、Kitaura J、Goyama S、Harada H、Aburatani H、Kitamura T
  • Journal Title: Leukemia Volume: 32 Issue: 2 Pages: 419-428
  • DOI: 10.1038/leu.2017.227
  • Peer Reviewed / Open Access
• [Presentation] Ceramide-CD300f interaction inhibits Mrgprb2-mediated pseudo-allergic drug reactions in mice (2019)
  • Author(s): 伊沢久未、高森絢子、貝谷綾子、安藤智暁、前原明絵、奥村康、北浦次郎
  • Organizer: 第68回日本アレルギー学会
• [Presentation] 喘息の病態形成における抑制型受容体CD300fの役割 (2019)
  • Author(s): 貝谷綾子、伊沢久未、安藤智暁、前原明絵、奥村康、北浦次郎
  • Organizer: 第68回日本アレルギー学会
• [Presentation] 経皮感作による食物アレルギーの病態メカニズム (2019)
  • Author(s): 山田啓迪、米山俊之、貝谷綾子、伊沢久未、安藤智暁、北浦次郎、奥村康、清水俊明
  • Organizer: 第43回日本小児皮膚科学会学術大会
  • Invited
• [Presentation] マウス及びヒトの免疫受容体 CD300f による脂質認識の違いは免疫グロブリン様ドメインの一アミノ酸変異に依存する (2019)
  • Author(s): 伊沢 久未、貝谷 綾子、奥村 康、北浦 次郎
  • Organizer: 第12回セラミド研究会学術集会
• [Presentation] Differential lipid recognition by mouse versus human CD300f, inhibiting IgE-mediated mast cell activation, depends on a single amino acid substitution in its immunoglobulin-like domain (2019)
  • Author(s): Ayako Kaitani, Kumi Izawa, Tomoaki Ando, Akie Maehara, Enzhi Yin, Moe Matsuzawa, Saaya Fukase, Hexing Wang, Keiko Maeda, Nobuhiro Nakano, Ko Okumura, Jiro Kitaura
  • Organizer: 第48回日本免疫学会
• [Presentation] Mast cell- and IgE-dependent anaphylaxis is regulated by the interaction between inhibitory LMIR3/activating LMIR7 and specific lipids (2019)
  • Author(s): Kumi Izawa, Ayako Kaitani, Tomoaki Ando, Akie Maehara, Takuma Ide, Moe Matsuzawa, Saaya Fukase, Anna Kamei, Taiki Ando, Nobuhiro Nakano, Ko Okumura Jiro Kitaura
  • Organizer: 第48回日本免疫学会
• [Presentation] Exaggerated inflammasome activation by a novel NLRP1 mutant derived from a rare disease with severe liver fibrosis (2019)
  • Author(s): Taiki Ando, Akie Maehara, Tomoaki Ando, Kumi Izawa, Ayako Kaitani, Enzhi Yin, Takuma Ide, Keiko Maeda, Nobuhiro Nakano, Naoto Tamura, Ko Okumura, Jiro Kitaura
  • Organizer: 第48回日本免疫学会
• [Presentation] Identification of inhibitory mechanisms in pseudo-allergy involving Mrgprb2/MRGPRX2-mediated mast cell activation (2019)
  • Author(s): Yoko Okamoto, Ayako Takamori, Kumi Izawa, Tomoaki Ando, Ayako Kaitani, Akie Maehara, Enzhi Yin, Hiromichi Yamada, Hexing Wang, Nobuhiro Nakano, Ko Okumura, Jiro Kitaura
  • Organizer: 第48回日本免疫学会
• [Presentation] An inhibitory receptor CD300f inhibits the pathogenesis of OVA-induced food allergy in mice (2019)
  • Author(s): Anna Kamei, Shino Uchida, Hiromichi Yamada, Kumi Izawa, Tomoaki Ando, Naoko Negishi, Akie Maehara, Ayako Kaitani, Yoko Okamoto, Nobuhiro Nakano, Ko Okumura, Jiro Kitaura
  • Organizer: 第48回日本免疫学会
• [Presentation] IgE- and mast cell-dependent anaphylactic responses are regulated by the CD300-lipid axis (2019)
  • Author(s): Jiro Kitaura, Kumi Izawa, Ayako Kaitani, Akie Maehara, Tomoaki Ando, Ko Okumura
  • Organizer: 第48回日本免疫学会
  • Invited
• [Presentation] The phytosphingosine-CD300b interaction promotes zymosan-induced, nitric oxide-dependent neutrophil recruitment (2019)
  • Author(s): 伊沢久未、高橋まり子、山西吉典、前原明絵、磯部優理、貝谷綾子、奥村康、金城雄樹、北村俊雄、北浦次郎
  • Organizer: 第28回東京免疫フォーラム
• [Presentation] CD300f suppresses neutrophil recruitment to LPS-injected skin: A role of CD300f in gram-negative bacterial skin infections? (2018)
  • Author(s): Ayako Kaitani, Kumi Izawa, Ayako Takamori, Shino Uchida, Ko Okumura, Jiro Kitaura.
  • Organizer: 第67回日本アレルギー学会
• [Presentation] IgE依存性食物アレルギーにおけるCD300fの役割の解明 (2018)
  • Author(s): 内田志野，高森絢子，貝谷綾子，奥村康，北浦次郎
  • Organizer: 第67回日本アレルギー学会
• [Presentation] ザイモサンによる好中球集積・炎症メカニズムの解明：NO産生樹状細胞におけるCD300bの役割 (2018)
  • Author(s): 伊沢久未，高森絢子，貝谷綾子，内田志野，奥村康，北浦次郎
  • Organizer: 第67回日本アレルギー学会
• [Presentation] ザイモサンによる好中球集積のメカニズムの解明：NO産生樹状細胞のCD300bが認識する脂質リガンドの役割 (2018)
  • Author(s): 伊沢久未、奥村康、北浦次郎
  • Organizer: 第11回セラミド研究会学術集会
• [Presentation] An inhibitory receptor CD300f regulates immune responses by binding to its ligand ceramide (2018)
  • Author(s): Jiro Kitaura, Kumi Izawa, Ko Okumura
  • Organizer: 第91回日本生化学会大会
  • Invited
• [Presentation] Ceramide-CD300f interaction in mast cells inhibits IgE-dependent and independent anaphylactic responses (2018)
  • Author(s): Jiro Kitaura
  • Organizer: 32nd Symposium of the Collegium Internationale Allergologium
  • Int'l Joint Research
• [Presentation] NO産生樹状細胞に発現するCD300bは脂質フィトスフィンゴシンを認識してザイモサン投与による好中球集積・関節炎を促進する (2018)
  • Author(s): 伊沢久未、高橋まり子、貝谷綾子、前原明絵、安藤智暁、北村俊雄、奥村康、北浦次郎
  • Organizer: 第46回日本臨床免疫学会総会
• [Presentation] Phytosphingosine-CD300b interaction promotes zymosan-induced nitric oxide-dependent neutrophil recruitment. (2018)
  • Author(s): Kumi Izawa, Mariko Takahashi, Ayako Kaitani, Akie Maehara, Tomoaki Ando, Atsushi Tanabe, Ko Okumura, Toshio Kitamura, Jiro Kitaura.
  • Organizer: 第47回日本免疫学会
• [Presentation] The role of CD300f in the development of asthma. (2018)
  • Author(s): Ayako Kaitani, Kumi Izawa, Tomoaki Ando, Akie Maehara, Atsushi Tanabe, Keiko Maeda, Novuhiro Nakano, Ko Okumura, Jiro Kitaura.
  • Organizer: 第47回日本免疫学会
• [Presentation] An inhivitory receptor CD300f suppresses the development of food allergy. (2018)
  • Author(s): Shino Uchida, Kumi Izawa, Koichiro Uchida, Naoko Negishi, Akie Maehara, Ayako Kaitani, Tomoaki Ando, Nobuhiro Nakano, Ko Okumura, Jiro Kitaura.
  • Organizer: 第47回日本免疫学会
• [Presentation] セラミドとLMIR3の結合はLPSにより誘導される皮膚炎症を抑制する (2017)
  • Author(s): 伊沢久未、高森絢子、奥村康、北浦次郎
  • Organizer: 第66回日本アレルギー学会学術大会
• [Presentation] LMIR3はマスト細胞を介するIgE非依存的な薬剤アレルギーを抑制する (2017)
  • Author(s): 高森絢子、伊沢久未、奥村康、北浦次郎
  • Organizer: 第66回日本アレルギー学会学術大会
• [Presentation] 腸管マスト細胞の形質発現におけるNotchシグナルの寄与 (2017)
  • Author(s): 中野信浩、北浦次郎、西山千春、八木田秀雄、奥村康、小川秀興
  • Organizer: 第66回日本アレルギー学会学術大会
• [Presentation] セラミドを認識する抑制型受容体CD300fによる炎症制御機構 (2017)
  • Author(s): 第12回STC研究会
  • Organizer: 北浦次郎
  • Invited
• [Presentation] 抑制型受容体CD300fとアレルギー疾患 (2017)
  • Author(s): 北浦次郎、伊沢久未、奥村康
  • Organizer: 第19回応用薬理シンポジウム
  • Invited
• [Presentation] Ceramide-CD300f interaction inhibits Mrgprb2-mediated mast cell activation and pseudo-allergic drug reactions in mice (2017)
  • Author(s): Ayako Takamori, Kumi Izawa, Akie Maehara, Ayako Kaitani, Shino Uchida, Jiro Kitaura
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] CD300f suppresses neutrophil recruitment to LPS-injected skin: A role of CD300f in gram-negative bacterial skin infections (2017)
  • Author(s): Ayako Kaitani, Kumi Izawa, Akie Maehara, Ayako Takamori, Shino Uchida, Jiro Kitaura
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Mast cell- and IgE-dependent anaphylaxis is regulated by paired receptors LMIR3 and LMIR7 (2017)
  • Author(s): Kumi Izawa, Akie Maehara, Ayako Kaitani, Ayako Takamori, Shino Uchida, Masamichi Isobe, Tomoaki Ando, Keiko Maeda, Nobuhiro Nakano, Ko Okumura, Toshio Kitamura, Jiro Kitaura
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] A critical role of an inhibitory receptor LMIR3 in the pathogenesis of food allergy (2017)
  • Author(s): Shino Uchida, Kumi Izawa, Koichiro Uchida, Naoko Negishi, Akie Maehara, Jiro Kitaura
  • Organizer: 第46回日本免疫学会学術集会
• [Book] セラミド研究の新展開（基礎から応用へ）、抑制型免疫受容体CD300fとセラミド＜セラミド研究の新展開～基礎から応用へ～＞ (2019)
  • Author(s): 伊沢久未、奥村康、北浦次郎
  • Total Pages: 7
  • Publisher: 食品化学新聞社(セラミド研究会）
  • ISBN: 9784916143358
• [Book] 薬剤による偽アレルギーにおけるCD300fの役割について (2019)
  • Author(s): 貝谷綾子、高森絢子、安藤智暁、伊沢久未、北浦次郎
  • Total Pages: 7
  • Publisher: 科学評論社、臨床免疫・アレルギー科
• [Book] 臨床免疫・アレルギー科 (2018)
  • Author(s): 伊沢久未、前原明絵、貝谷綾子、高森綾子、北浦次郎
  • Total Pages: 6
  • Publisher: 科学評論社
• [Remarks] I型アレルギー反応を即時に阻止する抗IgE抗体Fabの作製に成功
  • URL: https://www.juntendo.ac.jp/news/20181120-01.html
• [Remarks] 真菌成分が炎症を悪化させるメカニズムを解明
  • URL: https://www.juntendo.ac.jp/news/20190116-01.html
• [Remarks] 薬の副作用を抑えることに成功
  • URL: https://www.juntendo.ac.jp/news/20181115-01.html