Xianjun Xu1, Jinnian Cheng2, Shengzheng Luo1, Xiaoyuan Gong3, Dan Huang1, Jingxian Xu1, Yueqin Qian4, Xinjian Wan5, Hui Zhou6. 1. Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 2. Department of Gastroenterology, Shanghai General Hospital, Nanjing Medical University, Nanjing, China. 3. Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 4. Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. 5. Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. Electronic address: mdwanxinjian@126.com. 6. Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Gastroenterology, Shanghai General Hospital, Nanjing Medical University, Nanjing, China. Electronic address: mdzhouhui@163.com.
Abstract
RATIONALE: Spasmolytic polypeptide-expressing metaplasia (SPEM) is an important risk factor for the occurrence of gastric cancer. It may be driven by a chronic inflammatory environment in which macrophage is involved. Studies have shown that intestinal metaplasia may originate from SPEM, and bile acid-induced chronic inflammation plays an important role in the process of intestinal metaplasia. However, whether bile acids are involved in the development of SPEM and the specific mechanism are unclear. Meanwhile, macrophages are known to be involved in inflammation regulation by releasing various factors, including exosomes. In this study, we hypothesized that the exosomes released from macrophages stimulated by deoxycholic acid participated in the development of SPME. METHODS: In vivo, mice were gavaged with deoxycholic acid for 4 weeks, and gastric tissues were harvested. In vitro, deoxycholic acid-induced macrophage-derived exosomes were isolated by ultracentrifugation and cocultured with the gastric organoids of mice. Immunofluorescence staining and quantitative real-time PCR were used to analyze markers of macrophages and SPEM. RESULTS: In vivo, after 4 weeks of deoxycholic acid intragastric administration, macrophage markers (F4/80) and SPEM markers (TFF2 and GSII lectin) were increased in from treated mice compared with those from normal control mice. In vitro, macrophage-derived exosomes labeled with PKH67 were internalized by gastric organoids. Deoxycholic acid-induced macrophage-derived exosomes increased the expression of SPEM markers (TFF2 and GSII lectin) in gastric organoids compared to exosomes derived from macrophages without deoxycholic acid stimulation. CONCLUSION: Macrophage-derived exosomes may be a novel mechanism by which deoxycholic acid promotes SPEM.
RATIONALE: Spasmolytic polypeptide-expressing metaplasia (SPEM) is an important risk factor for the occurrence of gastric cancer. It may be driven by a chronic inflammatory environment in which macrophage is involved. Studies have shown that intestinal metaplasia may originate from SPEM, and bile acid-induced chronic inflammation plays an important role in the process of intestinal metaplasia. However, whether bile acids are involved in the development of SPEM and the specific mechanism are unclear. Meanwhile, macrophages are known to be involved in inflammation regulation by releasing various factors, including exosomes. In this study, we hypothesized that the exosomes released from macrophages stimulated by deoxycholic acid participated in the development of SPME. METHODS: In vivo, mice were gavaged with deoxycholic acid for 4 weeks, and gastric tissues were harvested. In vitro, deoxycholic acid-induced macrophage-derived exosomes were isolated by ultracentrifugation and cocultured with the gastric organoids of mice. Immunofluorescence staining and quantitative real-time PCR were used to analyze markers of macrophages and SPEM. RESULTS: In vivo, after 4 weeks of deoxycholic acid intragastric administration, macrophage markers (F4/80) and SPEM markers (TFF2 and GSII lectin) were increased in from treated mice compared with those from normal control mice. In vitro, macrophage-derived exosomes labeled with PKH67 were internalized by gastric organoids. Deoxycholic acid-induced macrophage-derived exosomes increased the expression of SPEM markers (TFF2 and GSII lectin) in gastric organoids compared to exosomes derived from macrophages without deoxycholic acid stimulation. CONCLUSION: Macrophage-derived exosomes may be a novel mechanism by which deoxycholic acid promotes SPEM.
Authors: Su-Mi Lee; Moon Sik Park; Seon-Young Park; Yoo-Duk Choi; Jin Ook Chung; Dong Hyun Kim; Young Do Jung; Hyun Soo Kim Journal: Mol Med Rep Date: 2022-02-16 Impact factor: 2.952