Research ArticleFibrosis

Eosinophil depletion suppresses radiation-induced small intestinal fibrosis

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Science Translational Medicine  21 Feb 2018:
Vol. 10, Issue 429, eaan0333
DOI: 10.1126/scitranslmed.aan0333

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Eosinophils foster fibrosis

Cancer patients receiving abdominal radiation can develop radiation-induced intestinal fibrosis (RIF). Takemura et al. observed eosinophils in the small intestine of RIF patients and irradiated mice. Lymphocyte-deficient mice still developed RIF, but eosinophils were indispensible. They probed the mechanism of interaction between stromal cells, and recruited eosinophils, and showed depletion of eosinophils with two types of antibodies that ameliorated RIF. As anti-eosinophil antibodies are moving forward clinically for other diseases, they may easily be repurposed to prevent RIF in cancer patients.

Abstract

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.

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