Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma

Hiroshi Higuchi; Natsuko Yamakawa; Ken Ichi Imadome; Takashi Yahata; Ryutaro Kotaki; Jun Ogata; Masatoshi Kakizaki; Koji Fujita; Jun Lu; Kazuaki Yokoyama; Kazuki Okuyama; Ai Sato; Masako Takamatsu; Natsumi Kurosaki; Syakira Mohamad Alba; Azran Azhim; Ryouichi Horie; Toshiki Watanabe; Toshio Kitamura; Kiyoshi Ando; Takao Kashiwagi; Toshimitsu Matsui; Akinao Okamoto; Hiroshi Handa; Masahiko Kuroda; Naoya Nakamura; Ai Kotani

doi:10.1182/blood-2017-07-794529

Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma

Hiroshi Higuchi
, Natsuko Yamakawa
, Ken Ichi Imadome
, Takashi Yahata
, Ryutaro Kotaki
, Jun Ogata
, Masatoshi Kakizaki
, Koji Fujita
, Jun Lu
, Kazuaki Yokoyama
, Kazuki Okuyama
, Ai Sato
, Masako Takamatsu
, Natsumi Kurosaki
, Syakira Mohamad Alba
, Azran Azhim
, Ryouichi Horie
, Toshiki Watanabe
, Toshio Kitamura
, Kiyoshi Ando

Takao Kashiwagi, Toshimitsu Matsui, Akinao Okamoto, Hiroshi Handa, Masahiko Kuroda, Naoya Nakamura, Ai Kotani

Research output: Contribution to journal › Article › peer-review

96 Scopus citations

Abstract

Epstein-Barr virus (EBV) causes various diseases in the elderly, including B-cell lymphoma such as Hodgkin's lymphoma and diffuse large B-cell lymphoma. Here, we show that EBV acts in trans on noninfected macrophages in the tumor through exosome secretion and augments the development of lymphomas. In a humanized mouse model, the different formation of lymphoproliferative disease (LPD) between 2 EBV strains (Akata and B95-8) was evident. Furthermore, injection of Akata-derived exosomes affected LPD severity, possibly through the regulation of macrophage phenotype in vivo. Exosomes collected from Akata-lymphoblastoid cell lines reportedly contain EBV-derived noncoding RNAs such as BamHI fragment A rightward transcript (BART) micro-RNAs (miRNAs) and EBVencoded RNA.We focused on the exosome-mediated delivery of BART miRNAs. In vitro, BART miRNAs could induce the immune regulatory phenotype in macrophages characterized by the gene expressions of interleukin 10, tumor necrosis factor-a, and arginase 1, suggesting the immune regulatory role of BART miRNAs.The expression level of an EBV-encoded miRNA was strongly linked to the clinical outcomes in elderly patients with diffuse large B-cell lymphoma.These results implicate BART miRNAs as 1 of the factors regulating the severity of lymphoproliferative disease and as a diagnostic marker for EBV1 B-cell lymphoma. (Blood. 2018;131(23):2552-2567).

Original language	English
Pages (from-to)	2552-2567
Number of pages	16
Journal	Blood
Volume	131
Issue number	23
DOIs	https://doi.org/10.1182/blood-2017-07-794529
State	Published - 7 Jun 2018
Externally published	Yes

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Higuchi, H., Yamakawa, N., Imadome, K. I., Yahata, T., Kotaki, R., Ogata, J., Kakizaki, M., Fujita, K., Lu, J., Yokoyama, K., Okuyama, K., Sato, A., Takamatsu, M., Kurosaki, N., Alba, S. M., Azhim, A., Horie, R., Watanabe, T., Kitamura, T., ... Kotani, A. (2018). Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma. Blood, 131(23), 2552-2567. https://doi.org/10.1182/blood-2017-07-794529

@article{78ec167ae03f45dcb53e57db828ec2f3,

title = "Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma",

abstract = "Epstein-Barr virus (EBV) causes various diseases in the elderly, including B-cell lymphoma such as Hodgkin's lymphoma and diffuse large B-cell lymphoma. Here, we show that EBV acts in trans on noninfected macrophages in the tumor through exosome secretion and augments the development of lymphomas. In a humanized mouse model, the different formation of lymphoproliferative disease (LPD) between 2 EBV strains (Akata and B95-8) was evident. Furthermore, injection of Akata-derived exosomes affected LPD severity, possibly through the regulation of macrophage phenotype in vivo. Exosomes collected from Akata-lymphoblastoid cell lines reportedly contain EBV-derived noncoding RNAs such as BamHI fragment A rightward transcript (BART) micro-RNAs (miRNAs) and EBVencoded RNA.We focused on the exosome-mediated delivery of BART miRNAs. In vitro, BART miRNAs could induce the immune regulatory phenotype in macrophages characterized by the gene expressions of interleukin 10, tumor necrosis factor-a, and arginase 1, suggesting the immune regulatory role of BART miRNAs.The expression level of an EBV-encoded miRNA was strongly linked to the clinical outcomes in elderly patients with diffuse large B-cell lymphoma.These results implicate BART miRNAs as 1 of the factors regulating the severity of lymphoproliferative disease and as a diagnostic marker for EBV1 B-cell lymphoma. (Blood. 2018;131(23):2552-2567).",

author = "Hiroshi Higuchi and Natsuko Yamakawa and Imadome, \{Ken Ichi\} and Takashi Yahata and Ryutaro Kotaki and Jun Ogata and Masatoshi Kakizaki and Koji Fujita and Jun Lu and Kazuaki Yokoyama and Kazuki Okuyama and Ai Sato and Masako Takamatsu and Natsumi Kurosaki and Alba, \{Syakira Mohamad\} and Azran Azhim and Ryouichi Horie and Toshiki Watanabe and Toshio Kitamura and Kiyoshi Ando and Takao Kashiwagi and Toshimitsu Matsui and Akinao Okamoto and Hiroshi Handa and Masahiko Kuroda and Naoya Nakamura and Ai Kotani",

note = "Publisher Copyright: {\textcopyright} 2018 by The American Society of Hematology.",

year = "2018",

month = jun,

day = "7",

doi = "10.1182/blood-2017-07-794529",

language = "English",

volume = "131",

pages = "2552--2567",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

number = "23",

}

Higuchi, H, Yamakawa, N, Imadome, KI, Yahata, T, Kotaki, R, Ogata, J, Kakizaki, M, Fujita, K, Lu, J, Yokoyama, K, Okuyama, K, Sato, A, Takamatsu, M, Kurosaki, N, Alba, SM, Azhim, A, Horie, R, Watanabe, T, Kitamura, T, Ando, K, Kashiwagi, T, Matsui, T, Okamoto, A, Handa, H, Kuroda, M, Nakamura, N & Kotani, A 2018, 'Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma', Blood, vol. 131, no. 23, pp. 2552-2567. https://doi.org/10.1182/blood-2017-07-794529

TY - JOUR

T1 - Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma

AU - Higuchi, Hiroshi

AU - Yamakawa, Natsuko

AU - Imadome, Ken Ichi

AU - Yahata, Takashi

AU - Kotaki, Ryutaro

AU - Ogata, Jun

AU - Kakizaki, Masatoshi

AU - Fujita, Koji

AU - Lu, Jun

AU - Yokoyama, Kazuaki

AU - Okuyama, Kazuki

AU - Sato, Ai

AU - Takamatsu, Masako

AU - Kurosaki, Natsumi

AU - Alba, Syakira Mohamad

AU - Azhim, Azran

AU - Horie, Ryouichi

AU - Watanabe, Toshiki

AU - Kitamura, Toshio

AU - Ando, Kiyoshi

AU - Kashiwagi, Takao

AU - Matsui, Toshimitsu

AU - Okamoto, Akinao

AU - Handa, Hiroshi

AU - Kuroda, Masahiko

AU - Nakamura, Naoya

AU - Kotani, Ai

PY - 2018/6/7

Y1 - 2018/6/7

N2 - Epstein-Barr virus (EBV) causes various diseases in the elderly, including B-cell lymphoma such as Hodgkin's lymphoma and diffuse large B-cell lymphoma. Here, we show that EBV acts in trans on noninfected macrophages in the tumor through exosome secretion and augments the development of lymphomas. In a humanized mouse model, the different formation of lymphoproliferative disease (LPD) between 2 EBV strains (Akata and B95-8) was evident. Furthermore, injection of Akata-derived exosomes affected LPD severity, possibly through the regulation of macrophage phenotype in vivo. Exosomes collected from Akata-lymphoblastoid cell lines reportedly contain EBV-derived noncoding RNAs such as BamHI fragment A rightward transcript (BART) micro-RNAs (miRNAs) and EBVencoded RNA.We focused on the exosome-mediated delivery of BART miRNAs. In vitro, BART miRNAs could induce the immune regulatory phenotype in macrophages characterized by the gene expressions of interleukin 10, tumor necrosis factor-a, and arginase 1, suggesting the immune regulatory role of BART miRNAs.The expression level of an EBV-encoded miRNA was strongly linked to the clinical outcomes in elderly patients with diffuse large B-cell lymphoma.These results implicate BART miRNAs as 1 of the factors regulating the severity of lymphoproliferative disease and as a diagnostic marker for EBV1 B-cell lymphoma. (Blood. 2018;131(23):2552-2567).

AB - Epstein-Barr virus (EBV) causes various diseases in the elderly, including B-cell lymphoma such as Hodgkin's lymphoma and diffuse large B-cell lymphoma. Here, we show that EBV acts in trans on noninfected macrophages in the tumor through exosome secretion and augments the development of lymphomas. In a humanized mouse model, the different formation of lymphoproliferative disease (LPD) between 2 EBV strains (Akata and B95-8) was evident. Furthermore, injection of Akata-derived exosomes affected LPD severity, possibly through the regulation of macrophage phenotype in vivo. Exosomes collected from Akata-lymphoblastoid cell lines reportedly contain EBV-derived noncoding RNAs such as BamHI fragment A rightward transcript (BART) micro-RNAs (miRNAs) and EBVencoded RNA.We focused on the exosome-mediated delivery of BART miRNAs. In vitro, BART miRNAs could induce the immune regulatory phenotype in macrophages characterized by the gene expressions of interleukin 10, tumor necrosis factor-a, and arginase 1, suggesting the immune regulatory role of BART miRNAs.The expression level of an EBV-encoded miRNA was strongly linked to the clinical outcomes in elderly patients with diffuse large B-cell lymphoma.These results implicate BART miRNAs as 1 of the factors regulating the severity of lymphoproliferative disease and as a diagnostic marker for EBV1 B-cell lymphoma. (Blood. 2018;131(23):2552-2567).

UR - https://www.scopus.com/pages/publications/85048267475

U2 - 10.1182/blood-2017-07-794529

DO - 10.1182/blood-2017-07-794529

M3 - Article

C2 - 29685921

AN - SCOPUS:85048267475

SN - 0006-4971

VL - 131

SP - 2552

EP - 2567

JO - Blood

JF - Blood

IS - 23

ER -

Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma

Abstract

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