CD226基因敲除加重小鼠放射性肝损伤的发生
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摘要
目的观察CD226基因敲除(KO)对小鼠放射性肝损伤的影响。方法雄性野生型(WT)和CD226KO小鼠随机分为非辐照组和辐照组,非辐照组不经过任何处理,辐照组接受8 Gy ~(60)Co照射建立急性放射性损伤模型。观察小鼠存活和体质量改变情况, HE染色观察肝脏和结肠病变情况,实时定量PCR检测肝和结肠组织炎症因子诱导型一氧化氮合酶(iNOS)、白细胞介素1β(IL-1β)、 IL-6、 IL-12p40、肿瘤坏死因子α(TNF-α)、单核细胞趋化蛋白1(MCP-1)的mRNA水平。结果与辐照WT小鼠相比,辐照后的CD226KO小鼠体质量明显下降,存活率下降; CD226KO小鼠肝脏损伤加重,肝指数(肝质量/体质量)下降显著, iNOS、 IL-1β、 IL-6、 IL-12p40、 TNF-α、 MCP-1 mRNA水平显著升高;但CD226KO小鼠结肠炎症减轻,炎症因子mRNA水平降低。结论 CD226缺失降低辐照小鼠存活率,与肝损伤加重密切相关。
Objective To investigate the effect of CD226 knockout(KO) on radiation-induced liver injury in mice. Methods Wild-type(WT) and CD226KO mice were randomly divided into naive group and irradiated group. The mice in the irradiated group were exposed to an 8 Gy of ~(60)Co γ-radiation. The survival rate was observed and body mass loss was measured. The pathological changes in the liver and colon were examined by HE staining, and the mRNA levels of inflammatory factors, including inducible nitric oxide synthase(iNOS), interleukin-1β(IL-1β), IL-6, IL-12p40, tumor necrosis factor α(TNF-α) and monocyte chemoattractant protein-1(MCP-1) were detected by real-time quantitative PCR. ResultsCompared with the irradiated WT mice, the irradiated CD226KO mice had increased body mass loss and decreased survival rate. In the irradiated CD226KO mice, the liver injury was more serious, the liver index(liver mass/body mass) was reduced, and the expressive levels of iNOS, IL-1β, IL-6, IL-12p40, TNF-α and MCP-1 were enhanced; whereas, the colitis was less serious, and the expressive levels of inflammatory factors were down-regulated. Conclusion The deficiency of CD226 can decrease the survival rate of irradiated mice, which is associated with the aggravated liver injury.
Objective To investigate the effect of CD226 knockout(KO) on radiation-induced liver injury in mice. Methods Wild-type(WT) and CD226KO mice were randomly divided into naive group and irradiated group. The mice in the irradiated group were exposed to an 8 Gy of ~(60)Co γ-radiation. The survival rate was observed and body mass loss was measured. The pathological changes in the liver and colon were examined by HE staining, and the mRNA levels of inflammatory factors, including inducible nitric oxide synthase(iNOS), interleukin-1β(IL-1β), IL-6, IL-12p40, tumor necrosis factor α(TNF-α) and monocyte chemoattractant protein-1(MCP-1) were detected by real-time quantitative PCR. ResultsCompared with the irradiated WT mice, the irradiated CD226KO mice had increased body mass loss and decreased survival rate. In the irradiated CD226KO mice, the liver injury was more serious, the liver index(liver mass/body mass) was reduced, and the expressive levels of iNOS, IL-1β, IL-6, IL-12p40, TNF-α and MCP-1 were enhanced; whereas, the colitis was less serious, and the expressive levels of inflammatory factors were down-regulated. Conclusion The deficiency of CD226 can decrease the survival rate of irradiated mice, which is associated with the aggravated liver injury.
引文
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[11] Kim K W, Williams J W, Wang Y T, et al. MHC Ⅱ+ resident peritoneal and pleural macrophages rely on IRF4 for development from circulating monocytes[J]. J Exp Med, 2016, 213(10): 1951-1959.
[12] Xu Z, Jin B. A novel interface consisting of homologous immunoglobulin superfamily members with multiple functions[J]. Cell Mol Immunol, 2010, 7(1): 11-19.
[13] Zhang Y, Liu T, Chen Y, et al. CD226 reduces endothelial cell glucose uptake under hyperglycemic conditions with inflammation in type 2 diabetes mellitus[J/OL]. Oncotarget, 2016, 7(11): 12010-12023.
[14] 王莉新, 吴文斌. NK细胞的免疫监视作用及肿瘤免疫逃逸[J]. 细胞与分子免疫学杂志, 2017, 33(3): 418-422. Wang L, Wu W. Immunosurveillance of NK cells and tumor immune escape[J]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi, 2017, 33(3): 418-422.
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[16] Gilfillan S, Chan C J, Cella M, et al. DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors[J]. J Exp Med, 2008, 205(13): 2965-2973.
[17] Chan C J, Martinet L, Gilfillan S, et al. The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions[J]. Nat Immunol, 2014, 15(5): 431-438.
[18] Zhang Z, Wu N, Lu Y, et al. DNAM-1 controls NK cell activation via an ITT-like motif[J]. J Exp Med, 2015, 212(12): 2165-2182.
[19] Kim Y S, Kim J, Park S J. High-throughput 16S rRNA gene sequencing reveals alterations of mouse intestinal microbiota after radiotherapy[J]. Anaerobe, 2015, 33: 1-7.
[20] Li M, Du A, Xu J, et al. Neurogenic differentiation factor NeuroD confers protection against radiation-induced intestinal injury in mice[J/OL]. Sci Rep, 2016, 6: 30180. DOI: 10.1038/srep30180.
[21] Li H, Liang Y, Lai X, et al. Genetic Deletion of Fbw7 in the mouse intestinal epithelium aggravated dextran sodium sulfate-induced colitis by modulating the inflammatory response of NF-kappaB pathway[J]. Biochem Biophys Res Commun, 2018, 498(4): 869-876.
[22] 朱玉贞, 戴军, 姚潇颖, 等. IL-16通过促进巨噬细胞的M1型极化加重葡聚糖硫酸钠诱导的小鼠炎症性肠病[J]. 细胞与分子免疫学杂志, 2018, 34(8): 695-701. Zhu Y, Dai J, Yao X, et al. IL-16 aggravates dextran sulfate sodium (DSS)-induced mouse inflammatory bowel disease by promoting M1 polarization of macrophages[J]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi, 2018, 34(8): 695-701.
[23] Arab J P, Martin-Mateos R M, Shah V H. Gut-liver axis, cirrhosis and portal hypertension: the chicken and the egg[J]. Hepatol Int, 2018, 12(Suppl 1): 24-33.
[24] Doi H, Kamikonya N, Takada Y, et al. Low-dose aspirin therapy does not increase the severity of acute radiation proctitis[J]. World J Oncol, 2012, 3(4): 173-181.
[25] McIlwain D R, Lang P A, Maretzky T, et al. iRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS[J]. Science, 2012, 335(6065): 229-232.
[26] Sullivan D P, Seidman M A, Muller W A. Poliovirus receptor (CD155) regulates a step in transendothelial migration between PECAM and CD99[J]. Am J Pathol, 2013, 182(3): 1031-1042.
[27] Reymond N, Imbert A M, Devilard E, et al. DNAM-1 and PVR regulate monocyte migration through endothelial junctions[J]. J Exp Med, 2004, 199(10): 1331-1341.
[28] Lenac Rovis T, Kucan Brlic P, Kaynan N, et al. Inflammatory monocytes and NK cells play a crucial role in DNAM-1-dependent control of cytomegalovirus infection[J]. J Exp Med, 2016, 213(9): 1835-1850.
[29] 胡伟, 庄然. 脂肪组织巨噬细胞研究进展[J]. 中国免疫学杂志, 2017, 33(11): 1723-1725. Hu W, Zhuang R. Recent advance in adipose tissue macrophages[J]. Zhongguo Mian Yi Xue Za Zhi, 2017, 33(11): 1723-1725.
[30] Chin A I, Dempsey P W, Bruhn K, et al. Involvement of receptor-interacting protein 2 in innate and adaptive immune responses[J]. Nature, 2002, 416(6877): 190-194.
[31] Vujaskovic Z, Thrasher B A, Jackson I L, et al. Radioprotective effects of amifostine on acute and chronic esophageal injury in rodents[J]. Int J Radiat Oncol Biol Phys, 2007, 69(2): 534-540.
[32] Aziz M H, Cui K, Das M, et al. The upregulation of integrin alphaDbeta2 (CD11d/CD18) on inflammatory macrophages promotes macrophage retention in vascular lesions and development of atherosclerosis[J]. J Immunol, 2017, 198(12): 4855-4867.
[33] Rotty J D, Brighton H E, Craig S L, et al. Arp2/3 complex is required for macrophage integrin functions but is dispensable for FcR phagocytosis and in vivo motility[J/OL]. Dev Cell, 2017, 42(5): 498-513.
[34] Wolf D, Anto-Michel N, Blankenbach H, et al. A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense[J/OL]. Nat Commun, 2018, 9(1): 525. DOI: 10.1038/s41467-018-02896-8.
[35] Bhanja P, Norris A, Gupta-Saraf P, et al. BCN057 induces intestinal stem cell repair and mitigates radiation-induced intestinal injury[J/OL]. Stem Cell Res Ther, 2018, 9(1): 26. DOI: 10.1186/s13287-017-0763-3.
[2] Koay E J, Owen D, Das P. Radiation-induced liver disease and modern radiotherapy[J]. Semin Radiat Oncol, 2018, 28(4): 321-331.
[3] Zappa M, Doblas S, Cazals-Hatem D, et al. Quantitative MRI in murine radiation-induced rectocolitis: comparison with histopathological inflammation score[J/OL]. NMR Biomed, 2018, 31(4): e3897. DOI: 10.1002/nbm.3897.
[4] Jang H, Park S, Lee J, et al. Rebamipide alleviates radiation-induced colitis through improvement of goblet cell differentiation in mice[J]. J Gastroenterol Hepatol, 2018, 33(4): 878-886.
[5] 江林宫, 孟鸿宇, 张火俊. 放射性肝损伤的研究进展[J]. 世界华人消化杂志, 2017, 25(20): 1811-1818. Jiang L, Meng H, Zhang H, et al. Advances in research of radiation-induced liver damage[J]. Shijie Hua Ren Xiao Hua Za Zhi, 2017, 25(20): 1811-1818.
[6] 闫鼎鼎, 楼寒梅. 放射性肠炎的内科防治新进展[J]. 中国现代医生, 2016, 54(10): 164-168. Yan D, Lou H. Recent progress in the medical treatment of radiation enteritis[J]. Zhongguo Xian Dai Yi Sheng, 2016, 54(10): 164-168.
[7] Shim S, Jang H S, Myung H W, et al. Rebamipide ameliorates radiation-induced intestinal injury in a mouse model[J]. Toxicol Appl Pharmacol, 2017, 329: 40-47.
[8] Cameron S, Schwartz A, Sultan S, et al. Radiation-induced damage in different segments of the rat intestine after external beam irradiation of the liver[J]. Exp Mol Pathol, 2012, 92(2): 243-258.
[9] Tan L, Dai T, Liu D, et al. Contribution of dermal-derived mesenchymal cells during liver repair in two different experimental models[J/OL]. Sci Rep, 2016, 6: 25314. DOI: 10.1038/srep25314.
[10] Tahara-Hanaoka S, Miyamoto A, Hara A, et al. Identification and characterization of murine DNAM-1 (CD226) and its poliovirus receptor family ligands[J]. Biochem Biophys Res Commun, 2005, 329(3): 996-1000.
[11] Kim K W, Williams J W, Wang Y T, et al. MHC Ⅱ+ resident peritoneal and pleural macrophages rely on IRF4 for development from circulating monocytes[J]. J Exp Med, 2016, 213(10): 1951-1959.
[12] Xu Z, Jin B. A novel interface consisting of homologous immunoglobulin superfamily members with multiple functions[J]. Cell Mol Immunol, 2010, 7(1): 11-19.
[13] Zhang Y, Liu T, Chen Y, et al. CD226 reduces endothelial cell glucose uptake under hyperglycemic conditions with inflammation in type 2 diabetes mellitus[J/OL]. Oncotarget, 2016, 7(11): 12010-12023.
[14] 王莉新, 吴文斌. NK细胞的免疫监视作用及肿瘤免疫逃逸[J]. 细胞与分子免疫学杂志, 2017, 33(3): 418-422. Wang L, Wu W. Immunosurveillance of NK cells and tumor immune escape[J]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi, 2017, 33(3): 418-422.
[15] 周博, 张栋梁, 刘雪芹, 等. CD226基因敲除小鼠血小板的结构异常与功能障碍[J]. 细胞与分子免疫学杂志, 2018, 34(4): 309-314. Zhou B, Zhang D, Liu X, et al. Abnormal structure and dysfunction of platelets in CD226 knockout mice[J]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi, 2018, 34(4): 309-314.
[16] Gilfillan S, Chan C J, Cella M, et al. DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors[J]. J Exp Med, 2008, 205(13): 2965-2973.
[17] Chan C J, Martinet L, Gilfillan S, et al. The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions[J]. Nat Immunol, 2014, 15(5): 431-438.
[18] Zhang Z, Wu N, Lu Y, et al. DNAM-1 controls NK cell activation via an ITT-like motif[J]. J Exp Med, 2015, 212(12): 2165-2182.
[19] Kim Y S, Kim J, Park S J. High-throughput 16S rRNA gene sequencing reveals alterations of mouse intestinal microbiota after radiotherapy[J]. Anaerobe, 2015, 33: 1-7.
[20] Li M, Du A, Xu J, et al. Neurogenic differentiation factor NeuroD confers protection against radiation-induced intestinal injury in mice[J/OL]. Sci Rep, 2016, 6: 30180. DOI: 10.1038/srep30180.
[21] Li H, Liang Y, Lai X, et al. Genetic Deletion of Fbw7 in the mouse intestinal epithelium aggravated dextran sodium sulfate-induced colitis by modulating the inflammatory response of NF-kappaB pathway[J]. Biochem Biophys Res Commun, 2018, 498(4): 869-876.
[22] 朱玉贞, 戴军, 姚潇颖, 等. IL-16通过促进巨噬细胞的M1型极化加重葡聚糖硫酸钠诱导的小鼠炎症性肠病[J]. 细胞与分子免疫学杂志, 2018, 34(8): 695-701. Zhu Y, Dai J, Yao X, et al. IL-16 aggravates dextran sulfate sodium (DSS)-induced mouse inflammatory bowel disease by promoting M1 polarization of macrophages[J]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi, 2018, 34(8): 695-701.
[23] Arab J P, Martin-Mateos R M, Shah V H. Gut-liver axis, cirrhosis and portal hypertension: the chicken and the egg[J]. Hepatol Int, 2018, 12(Suppl 1): 24-33.
[24] Doi H, Kamikonya N, Takada Y, et al. Low-dose aspirin therapy does not increase the severity of acute radiation proctitis[J]. World J Oncol, 2012, 3(4): 173-181.
[25] McIlwain D R, Lang P A, Maretzky T, et al. iRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS[J]. Science, 2012, 335(6065): 229-232.
[26] Sullivan D P, Seidman M A, Muller W A. Poliovirus receptor (CD155) regulates a step in transendothelial migration between PECAM and CD99[J]. Am J Pathol, 2013, 182(3): 1031-1042.
[27] Reymond N, Imbert A M, Devilard E, et al. DNAM-1 and PVR regulate monocyte migration through endothelial junctions[J]. J Exp Med, 2004, 199(10): 1331-1341.
[28] Lenac Rovis T, Kucan Brlic P, Kaynan N, et al. Inflammatory monocytes and NK cells play a crucial role in DNAM-1-dependent control of cytomegalovirus infection[J]. J Exp Med, 2016, 213(9): 1835-1850.
[29] 胡伟, 庄然. 脂肪组织巨噬细胞研究进展[J]. 中国免疫学杂志, 2017, 33(11): 1723-1725. Hu W, Zhuang R. Recent advance in adipose tissue macrophages[J]. Zhongguo Mian Yi Xue Za Zhi, 2017, 33(11): 1723-1725.
[30] Chin A I, Dempsey P W, Bruhn K, et al. Involvement of receptor-interacting protein 2 in innate and adaptive immune responses[J]. Nature, 2002, 416(6877): 190-194.
[31] Vujaskovic Z, Thrasher B A, Jackson I L, et al. Radioprotective effects of amifostine on acute and chronic esophageal injury in rodents[J]. Int J Radiat Oncol Biol Phys, 2007, 69(2): 534-540.
[32] Aziz M H, Cui K, Das M, et al. The upregulation of integrin alphaDbeta2 (CD11d/CD18) on inflammatory macrophages promotes macrophage retention in vascular lesions and development of atherosclerosis[J]. J Immunol, 2017, 198(12): 4855-4867.
[33] Rotty J D, Brighton H E, Craig S L, et al. Arp2/3 complex is required for macrophage integrin functions but is dispensable for FcR phagocytosis and in vivo motility[J/OL]. Dev Cell, 2017, 42(5): 498-513.
[34] Wolf D, Anto-Michel N, Blankenbach H, et al. A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense[J/OL]. Nat Commun, 2018, 9(1): 525. DOI: 10.1038/s41467-018-02896-8.
[35] Bhanja P, Norris A, Gupta-Saraf P, et al. BCN057 induces intestinal stem cell repair and mitigates radiation-induced intestinal injury[J/OL]. Stem Cell Res Ther, 2018, 9(1): 26. DOI: 10.1186/s13287-017-0763-3.