Eosinophil depletion suppresses radiation-induced small intestinal fibrosis

Naoki Takemura, Yosuke Kurashima, Yuki Mori, Kazuki Okada, Takayuki Ogino, Hideki Osawa, Hirosih Matsuno, Lamichhane Aayam, Satoshi Kaneto, Eun Jeong Park, Shintaro Sato, Kouta Matsunaga, Yusuke Tamura, Yasuo Ouchi, Yutaro Kumagai, Daichi Kobayashi, Yutaka Suzuki, Yoshichika Yoshioka, Junichi Nishimura, Masaki MoriKen J. Ishii, Mark E. Rothenberg, Hiroshi Kiyono, Shizuo Akira, Satoshi Uematsu

研究成果: Contribution to journalArticle

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Radiation-induced intestinal fibrosis (RIF) is a serious complication after abdominal radiotherapy for pelvic tumor or peritoneal metastasis. Herein, we show that RIF is mediated by eosinophil interactions with α-smooth muscle actin-positive (α-SMA+) stromal cells. Abdominal irradiation caused RIF especially in the submucosa (SM) of the small intestine, which was associated with the excessive accumulation of eosinophils in both human and mouse. Eosinophil-deficient mice showed markedly ameliorated RIF, suggesting the importance of eosinophils. After abdominal irradiation, chronic crypt cell death caused elevation of extracellular adenosine triphosphate, which in turn activated expression of C-C motif chemokine 11 (CCL11) by pericryptal α-SMA+ cells in the SM to attract eosinophils in mice. Inhibition of C-C chemokine receptor 3 (CCR3) by genetic deficiency or neutralizing antibody (Ab) treatment suppressed eosinophil accumulation in the SM after irradiation in mice, suggesting a critical role of the CCL11/CCR3 axis in the eosinophil recruitment. Activated α-SMA+ cells also expressed granulocyte-macrophage colony-stimulating factor (GM-CSF) to activate eosinophils. Transforming growth factor-β1 from GM-CSF-stimulated eosinophils promoted collagen expression by α-SMA+ cells. In translational studies, treatment with a newly developed interleukin-5 receptor α-targeting Ab, analogous to the human agent benralizumab, depleted intestinal eosinophils and suppressed RIF in mice. Collectively, we identified eosinophils as a crucial factor in the pathogenesis of RIF and showed potential therapeutic strategies for RIF by targeting eosinophils.

元の言語英語
記事番号eaan0333
ジャーナルScience Translational Medicine
10
発行部数429
DOI
出版物ステータス出版済み - 2 21 2018
外部発表Yes

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Takemura, N., Kurashima, Y., Mori, Y., Okada, K., Ogino, T., Osawa, H., Matsuno, H., Aayam, L., Kaneto, S., Park, E. J., Sato, S., Matsunaga, K., Tamura, Y., Ouchi, Y., Kumagai, Y., Kobayashi, D., Suzuki, Y., Yoshioka, Y., Nishimura, J., ... Uematsu, S. (2018). Eosinophil depletion suppresses radiation-induced small intestinal fibrosis. Science Translational Medicine, 10(429), [eaan0333]. https://doi.org/10.1126/scitranslmed.aan0333