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

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15 Citations (Scopus)

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 languageEnglish
Pages (from-to)2552-2567
Number of pages16
JournalBlood
Volume131
Issue number23
DOIs
Publication statusPublished - 07-06-2018

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

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