Elucidation of control mechanism of skin inflammatory diseases involving TLRs

• Project/Area Number: 17K16352
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Dermatology
• Research Institution: Juntendo University
• Principal Investigator: Izawa Kumi 順天堂大学, 医学(系)研究科(研究院), 助教 (80708313)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: CD300 / TLR / LPS / ceramide / zymosan / ペア型レセプター / アレルギー

Outline of Final Research Achievements

A rapid accumulation of neutrophils with edema was observed in the ear skin of CD300f KO mice compared with WT mice 1 day after E. coli inoculation. However, skin inflammation, characterized by edema and neutrophil accumulation, subsided in the ear skin of CD300f KO mice 6 days after E. coli inoculation, presumably because E. coli was cleared by rapidly recruited neutrophils. We observed persistent inflammation after E. coli infection in the ear skin of WT mice and lower counts of E. coli were noted in the ears of CD300f KO mice 5 days after E. coli inoculation. Furthermore,we found that treatment with anti-ceramide Ab, but not with a control Ab, disrupted the ceramide-CD300f interaction and lowered the counts of E. coli in the inoculated ear skin of WT mice 5 days after E. coli inoculation at levels comparable to those of CD300f KO mice. Disrupting the ceramide-CD300f interaction promote the recruitment of neutrophils to sites of infection that efficiently engulf and kill E. coli.

Academic Significance and Societal Importance of the Research Achievements

CD300f欠損マウスは盲腸結紮穿刺による敗血症性腹膜炎に対して抵抗性を示し、野生型マウスに対するセラミド抗体やCD300f-Fcの投与は敗血症性腹膜炎の致死率を改善させることが証明されている。今回、大腸菌の皮膚感染ではセラミドとCD300fの結合は好中球遊走因子の産生を抑制して好中球集積を抑えるため、感染防御には不利に働いた。また、セラミド抗体の投与は腹膜炎モデル同様に、皮膚における大腸菌の排除を改善させた。ヒトCD300fにおいても同様の結果が得られ、セラミドとCD300fの結合を阻害する薬剤はグラム陰性桿菌感染（皮膚及び全身）の治療薬として有効である可能性が示唆された。

Research Products

• [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] 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] 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] 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] セラミドと皮膚アレルギー・炎症 (2018)
  • Author(s): 貝谷綾子、前原明絵、高森綾子、伊沢久未、北浦次郎
  • Journal Title: 臨床免疫・アレルギー科 Volume: 69 Pages: 576-582
  • Peer Reviewed
• [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] 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] 敗血症性腹膜炎におけるCD300fとセラミドの役割 (2018)
  • Author(s): 伊沢久未、前原明絵、貝谷綾子、高森綾子、北浦次郎
  • Journal Title: 臨床免疫・アレルギー科 Volume: 69:3 Pages: 250-256
  • Peer Reviewed
• [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
• [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] 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] 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] A novel mutation of NLRP1 is involved in the pathogenesis of a rare disease with severe liver fibrosis. (2018)
  • Author(s): Taiki Ando, Akie Maehara, Tomoaki Ando, Kumi, Izawa, Ayako Kaitani, Atsushi Tanabe, Keiko Maeda, Novuhiro Nakano, Naoto Tamura, Ko Okumura, Jiro Kitaura.
  • Organizer: 第47回日本免疫学会
• [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] 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] Identification and characterization of a novel mutation of NLRP1 in a patient with a rare disease involving severe liver fibrosis. (2018)
  • Author(s): Akie Maehara, Hiroki Yasudo, Atsushi Tanabe, Tomoaki Ando, Kumi Izawa, Ayako Kaitani, Ayako Takamori, Shino Uchida, Keiko Maeda, Nobuhiro Nakano, Ko Okumura, Jiro Kitaura.
  • Organizer: Australia-Japan Meeting on Cell Death.
  • Int'l Joint Research
• [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] 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
• [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, Atsushi Tanabe, Tomoaki Ando, Keiko Maeda, Nobuhiro Nakano, Toshio Kitamura, Ko Okumura, 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, Atsushi Tanabe, 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] Identification and characterization of a novel mutation of NLRP1 in a patient with a rare disease involving severe liver fibrosis (2017)
  • Author(s): Akie Maehara, Atsushi Tanabe, Tomoaki Ando, Kumi Izawa, Ayako Kaitani, Ayako Takamori, Shino Uchida, Keiko Maeda, Nobuhiro Nakano, Ko Okumura, 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, Ayako Kaitani, Ayako Takamori, Tomoaki Ando, Nobuhiro Nakano, Toshio Kitamura, Ko Okumura, Jiro Kitaura
  • Organizer: 第46回日本免疫学会学術集会