| First Author | Takemura N | Year | 2018 |
| Journal | Sci Transl Med | Volume | 10 |
| Issue | 429 | PubMed ID | 29467297 |
| Mgi Jnum | J:260049 | Mgi Id | MGI:6117602 |
| Doi | 10.1126/scitranslmed.aan0333 | Citation | Takemura N, et al. (2018) Eosinophil depletion suppresses radiation-induced small intestinal fibrosis. Sci Transl Med 10(429) |
| abstractText | 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 alpha-smooth muscle actin-positive (alpha-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 alpha-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 alpha-SMA(+) cells also expressed granulocyte-macrophage colony-stimulating factor (GM-CSF) to activate eosinophils. Transforming growth factor-beta1 from GM-CSF-stimulated eosinophils promoted collagen expression by alpha-SMA(+) cells. In translational studies, treatment with a newly developed interleukin-5 receptor alpha-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. |
