Eosinophil depletion suppresses radiation-induced small intestinal fibrosis

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.

Deciphering the role of eosinophils in solid organ transplantation

“…In fact, BAL eosinophilia has been used to predict a form of graft fibrosis defined as restrictive CLAD . In murine models, the role of eosinophil‐mediated fibrosis has been linked to their promotion of collagen expression in epithelial cells through production of transforming growth factor‐β after therapeutic radiation in the gut, another mucosal barrier organ . In asthma models, eosinophils were demonstrated as being dispensable for airway hyperresponsiveness and mucous secretion, but critical for peribronchial collagen deposition .…”

“…71,87 In murine models, the role of eosinophil-mediated fibrosis has been linked to their promotion of collagen expression in epithelial cells through production of transforming growth factor-β after therapeutic radiation in the gut, another mucosal barrier organ. 88 In asthma models, eosinophils were demonstrated as being dispensable for airway hyperresponsiveness and mucous secretion, but critical for peribronchial collagen deposition. 89 Thus, our recent proposal to facilitate lung allograft acceptance through increased eosinophil migration into the lung 75 might come with a price of long-term CLAD.…”

ATP as a Pathophysiologic Mediator of Bacteria-Host Crosstalk in the Gastrointestinal Tract

“…For example, mice with hapten-induced colitis had increased levels of eATP in the intestinal lumen [18]. Moreover, eATP concentrations also increase during other intestinal inflammatory states, including graft-versus-host disease and irradiation-induced abdominal fibrosis [54,55]. …”

“…These observations show that P2X7R is involved in chronic inflammation, such as fibrosis in various tissues (e.g., lung, kidney, and pancreas) [78]. In this regard, radiation-induced injury of small-intestinal epithelial cells led to increased eATP release due to cryptal cell death [55]; increased eATP release in the cryptal region occurred for at least several weeks. In addition, eATP stimulated excess collagen expression by myofibroblasts positive for α-smooth muscle actin and led to the induction of eosinophils via the release of granulocyte-macrophage colony-stimulating factor.…”

“…In addition, eATP stimulated excess collagen expression by myofibroblasts positive for α-smooth muscle actin and led to the induction of eosinophils via the release of granulocyte-macrophage colony-stimulating factor. This chronic fibrogenic loop led to irradiation-induced intestinal fibrosis [55]. Although fibrosis typically is a component of healing of injured tissue, accumulated evidence suggests that eATP is involved in detrimental fibrosis rather than healing in the gut.…”