Analysis of role of PILRalpha in monocyte infiltration and of its physiological significance in vivo

• Project/Area Number: 15K08531
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Osaka University
• Principal Investigator: Kohyama (Ise) Masako (2018) 大阪大学, 微生物病研究所, 助教 (40598885); 伊勢 雅子 (香山雅子) 大阪大学, 微生物病研究所, 助教 (70311339)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 単球 / 浸潤 / 肥満

Outline of Final Research Achievements

Paired immunoglobulin-like type 2 receptorα (PILRα) is an inhibitory receptor that is mainly expressed on myeloid cells, and negatively regulates neutrophil infiltration during inflammation. However, its role on monocyte has remained unknown. Under both steady-state and inflammatory conditions, monocytes migrate into tissues and differentiate into macrophages. Macrophages in adipose and liver tissues play important roles in tissue homeostasis and pathogenesis of metabolic diseases. We found that PILRα controls monocyte mobility through regulating integrin signaling and inhibiting CD99-CD99 binding. Moreover, we found that Pilra-/- mice develop obesity and hepatomegaly with fibrosis, and the numbers of macrophages in adipose and liver tissues are significantly increased in Pilra-/- mice. These data suggest that immune inhibitory receptor, PILRα, plays an important role in the prevention of obesity and liver fibrosis.

Academic Significance and Societal Importance of the Research Achievements

現代病とも言えるメタボリックシンドロームに関連する疾患において、疾患局所に浸潤し組織固有の機能を持ったマクロファージに分化する能力を有する単球が注目されている。申請者らはPILRα分子が単球の組織への浸潤を抑制的に制御していることが明らかにした。このことは逆に、脂肪組織あるいは肝臓への単球の浸潤を防ぐことができれば、肥満や肝臓の繊維化を抑制できることを意味している。つまり申請者らによって明らかとなったPILRα分子による単球の動態の制御によって、これらの疾患の予防あるいは治療に繋げられる成果だと考えている。

Research Products

• [Journal Article] Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles. (2018)
  • Author(s): Kayama H, Kohyama M, Okuzaki D, Motooka D, Barman S, Okumura R, Muneta M, Hoshino K, Sasaki I, Ise W, Matsuno H, Nishimura J, Kurosaki T, Nakamura S, Arase H, Kaisho T, Takeda K.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 115 Issue: 33 Pages: 8418-8423
  • DOI: 10.1073/pnas.1808426115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 脾臓や肝臓の組織マクロファージとその分化制御機構 (2018)
  • Author(s): 香山雅子
  • Journal Title: 炎症と免疫 Volume: 26 Pages: 192-196
• [Journal Article] Immune evasion of Plasmodium falciparum by RIFIN via inhibitory receptors (2017)
  • Author(s): Saito Fumiji、Hirayasu Kouyuki、Satoh Takeshi、Wang Christian W.、Lusingu John、Arimori Takao、Shida Kyoko、Palacpac Nirianne Marie Q.、Itagaki Sawako、Iwanaga Shiroh、Takashima Eizo、Tsuboi Takafumi、Kohyama Masako、Suenaga Tadahiro、Colonna Marco、Takagi Junichi、Lavstsen Thomas、Horii Toshihiro、Arase Hisashi
  • Journal Title: Nature. Volume: 552 Issue: 7683 Pages: 101-105
  • DOI: 10.1038/nature24994
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Myeloperoxidase/HLA Class II Complexes Recognized by Autoantibodies in Microscopic Polyangiitis (2017)
  • Author(s): Hiwa Ryosuke、Ohmura Koichiro、Arase Noriko、Jin Hui、Hirayasu Kouyuki、Kohyama Masako、Suenaga Tadahiro、Saito Fumiji、Terao Chikashi、Atsumi Tatsuya、Iwatani Hirotsugu、Mimori Tsuneyo、Arase Hisashi
  • Journal Title: Arthritis Rheumatol. Volume: 69 Issue: 10 Pages: 2069-2080
  • DOI: 10.1002/art.40170
  • Peer Reviewed
• [Journal Article] Monocyte infiltration into obese and fibrilized tissues is regulated by PILRα. (2016)
  • Author(s): Kohyama M, Matsuoka S, Shida K, Sugihara F, Aoshi T, Kishida K, Ishii KJ, Arase H.
  • Journal Title: Eur J Immunol. Volume: in press Issue: 5 Pages: 1214-1223
  • DOI: 10.1002/eji.201545897
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] RAG-mediated DNA double-strand breaks activate a cell type-specific checkpoint to inhibit pre-B cell receptor signals. (2016)
  • Author(s): Bednarski JJ, Pandey R, Schulte E, White LS, Chen BR, Sandoval GJ, Kohyama M, Haldar M, Nickless A, Trott A, Cheng G, Murphy KM, Bassing CH, Payton JE, Sleckman BP.
  • Journal Title: RAG-mediated DNA double-strand breaks activate a cell type-specific checkpoint to inhibit pre-B cell receptor signals. Volume: 213 Issue: 2 Pages: 209-223
  • DOI: 10.1084/jem.20151048
  • Peer Reviewed
• [Journal Article] Sialic Acids on Varicella-Zoster Virus Glycoprotein B Are Required for Cell-Cell Fusion. (2015)
  • Author(s): Suenaga T, Matsumoto M, Arisawa F, Kohyama M, Hirayasu K, Mori Y, Arase H.
  • Journal Title: J Biol Chem. Volume: 290 Issue: 32 Pages: 19833-19843
  • DOI: 10.1074/jbc.m114.635508
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] T細胞レセプターと同様な抗原特異性を示す抗体による新たな免疫制御機構 (2018)
  • Author(s): 岸田 一輝, 香山雅子, 末永忠広, 荒瀬 尚
  • Organizer: 第28 回Kyoto T cell Conference
• [Presentation] Host Molecules Associating with Human Herpesvirus 6(HHV-6 (2018)
  • Author(s): Yuriko Muramatsu, Tadahiro Suenaga, Masako Kohyama, Hisashi Arase
  • Organizer: 第17回あわじしま感染症・免疫フォーラム
  • Int'l Joint Research
• [Presentation] Glycosylation of glycoprotein B is involved in tropism of herpes simplex virus (2018)
  • Author(s): Akihito Sakoguchi,Tadahiro Suenaga,Yasushi Kawaguchi,Hisashi Arase
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] 糖鎖認識機構を介した PILRaの単球における役割解析 (2017)
  • Author(s): 香山 雅子
  • Organizer: 糖鎖免疫 Glyco-Immunology 2017
  • Place of Presentation: 東京医科歯科大学（東京）
  • Year and Date: 2017-01-25
• [Presentation] Microbially cleaved immunoglobulins are sensed by the innate immune receptor LILRA2 (2017)
  • Author(s): Kouyuki Hirayasu, Fumiji Saito, Tadahiro Suenaga, Kyoko Shida, Noriko Aras, Keita Oikawa, Toshifumi Yamaoka, Hiroyuki Murota, Hiroji Chibana, Ichiro Nakagawa, Tomoko Kubori, Hiroki Nagai, Yuji Nakamaru, Ichiro Katayama, Marco Colonna, Hisashi Arase.
  • Organizer: Cytokines 2017 in Kanazawa, Japan
  • Int'l Joint Research
• [Presentation] Crucial role of CD74 in hematopoietic cell differentiation (2017)
  • Author(s): Tatsuya Shishido, Masako Kohyama, Kouyuki Hirayasu, Tadahiro Suenaga, Hisashi Arase
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Immune evasion of Plasmodium falciparum by RIFIN via inhibitory receptors (2017)
  • Author(s): Fumiji Saito, Kouyuki Hirayasu, Takeshi Satoh, Christian W. Wang, John Lusingu, Shiroh Iwanaga, Takafumi Tsuboi, Marco Colonna, Junichi Takagi, Thomas Lavstsen, Toshihiro Horii, Hisashi Arase
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Chemical compounds that specifically inhibit aberrant MHC class II expression (2017)
  • Author(s): Yuta Shimizu, Kyoko Shida, Kouyuki Hirayasu, Masako Kohyama, Tadahiro Suenaga, Hisashi Arase
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Antigen-specific immune regulation mediated by TCR-like antibodies (2017)
  • Author(s): Kazuki Kishida, Kouyuki Hirayasu, Masako Kohyama, Tadahiro Suenaga, Hisashi Arase
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Antiphospholipid antibody recognizes β2GPI complexed with HLA class II molecules via its domain V (2017)
  • Author(s): Yuki Sasagawa, Kenji Tanimura, Hui Jin, Noriko Arase, Tadahiro Suenaga, Masako Kohyama, Kouyuki Hirayasu, Satoko Morikami, Yasuhiko Ebina, Tatsuya Atsumi, Hideto Yamada, Hisashi Arase
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Prothrombin complexed with HLA class II molecules is an autoantibody target in antiphospholipid syndrome (2017)
  • Author(s): Satoko Morikami, Kenji Tanimura, Noriko Arase, Kouyuki Hirayasu, Tadahiro Suenaga, Masako Kohyama, Tatsuya Atsumi, Hideto Yamada, Hisashi Arase
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Intestinal Epithelial Homeostasis Regulated by CD74 (2017)
  • Author(s): Masako Kohyama, Sumiko Matsuoka, Tatsuya Shishido, Hisashi Arase
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Induction of autoantibody by neo-self TSH receptor / MHC class II complexes (2016)
  • Author(s): Hui Jin, Noriko Arase, Sumiko Matsuoka, Kouyuki Hirayasu, Masako Kohyama, Tadahiro Suenaga, Takehiko Sasazuki and Hisashi Arase
  • Organizer: 第45日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター（沖縄）
  • Year and Date: 2016-12-05
• [Presentation] Myeloperoxidase/HLA class II complexes are targets for autoantibodies in ANCA-associated vasculitis (2015)
  • Author(s): Hiwa Ryosuke, Ohmura Koichiro, Arase Noriko, Jin Hui, Hirayasu Kouyuki, Kohayama Masako, Suenaga Tadahiro, Saito Fumiji, Iwatani Hirotsugu, Atsumi Tatsuya, Terao Chikashi, Mimori Tsuneyo, Arase Hisashi
  • Organizer: 第44日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2015-12-18
• [Presentation] PILRα negatively regulates monocyte infiltration into the skin (2015)
  • Author(s): Kohyama Masako, Matsuoka Sumiko, Arase Noriko, Arase Hisashi
  • Organizer: 第44日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2015-12-18
• [Presentation] MHC class II molecules expose autoantibody epitopes on autoantigens (2015)
  • Author(s): Jin Hui, Arase Noriko, Matsuoka Sumiko, Hirayasu Kouyuki, Kohayama Masako, Suenaga Tadahiro, Sasazuki Takehiko, Arase Hisashi
  • Organizer: 第44日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2015-12-18
• [Presentation] 食餌鉄依存的な腸管CX3CR1high制御性ミエロイド細胞維持機構 (2015)
  • Author(s): 香山尚子, 香山雅子, 竹田潔
  • Organizer: 第43回日本臨床免疫学会総会
  • Place of Presentation: 神戸国際会議場(兵庫）
  • Year and Date: 2015-10-22
• [Presentation] MPO/HLA classⅡ複合体は顕微鏡的多発血管炎における自己抗体の標的である (2015)
  • Author(s): 日和良介, 大村浩一郎, 荒瀬規子, 金暉, 平安恒幸, 香山雅子, 末永忠広, 齋藤史路, 岩谷博次, 渥美達也, 寺尾知可史, 三森経世, 荒瀬尚
  • Organizer: 第43回日本臨床免疫学会総会
  • Place of Presentation: 神戸国際会議場(兵庫）
  • Year and Date: 2015-10-22
• [Remarks] 免疫化学分野ホームページ
  • URL: http://immchem.biken.osaka-u.ac.jp
• [Remarks] 大阪大学微生物病研究所免疫化学分野ホームページ
  • URL: http://immchem.biken.osaka-u.ac.jp