Protective effects of flagellin A N/C against radiation-induced NLR pyrin domain containing 3 inflammasome-dependent pyroptosis in intestinal cells

Publication date: Available online 31 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Dongming Wu, Rong Han, Shihua Deng, Teng Liu, Ting Zhang, Hongxiang Xie, Ying Xu
PurposeRadiation-induced enteropathy is among the most prevalent dose-limiting radiation toxicities. Despite its prevalence and burden, there are currently no effective treatments for radiation-induced intestinal injury, and understanding of this pathology remains poor. The present study aimed to investigate changes induced in mouse intestines after irradiation and to explore the potential radioprotective effects of flagellin A (FlaA) N/C.MethodsA mouse model of radiation-induced enteropathy was used in this study. A 10 Gy abdominal irradiation was performed on FlaA N/C- and vehicle-injected mice to explore the role of FlaA N/C in intestinal radiation injury and to study the molecular mechanism in this process. In the intestinal tissue, pathological changes were investigated by hematoxylin and eosin staining, TUNEL staining, and immunohistochemistry; western blotting and quantitative reverse transcription polymerase chain reaction were used to determine the changes in protein and mRNA levels, respectively; and an enzyme-linked immunosorbent assay was performed to determine protein concentration in serum. The involvement of the ROS pathway was investigated by determining superoxide dismutase, glutathione (GSH) peroxidase, GSH reductase (GR), and GSH disulfide (GSSG) plus GSH (GSSG + GSH) activities.ResultsFlaAN/C inhibited radiation-induced ROS production, decreased NLRP3 activity, and reduced the occurrence of caspase-1-dependent pyroptosis. The results revealed that oxidative stress, bioenergetic impairment, and subsequent NLRP3 inflammasome activation were involved in radiation-induced intestinal injury. FlaAN/C exerted a protective effect by blunting the activation of NLRP3 inflammasome signaling, thereby reducing the inflammatory response and occurrence of caspase-1-dependent pyroptosis in the intestine. Therefore, treatment of mice with FlaAN/C reduced radiation-induced intestinal injury.ConclusionROS-induced NLRP3 inflammasomes mediated radiation-induced pyroptosis of the intestinal cells, and FlaAN/C suppressed pyroptosis to protect the intestinal tissue. These results provide novel insights into the mechanisms underlying radiation-induced cytotoxicity, and FlaAN/C might be a potential preventive therapy for radiation-induced intestinal injury in patients with cancer.



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