Gut-Derived Exosomes Induce Liver Injury After Intestinal Ischemia/Reperfusion by Promoting Hepatic Macrophage Polarization
Gut-Derived Exosomes Induce Liver Injury After Intestinal Ischemia/Reperfusion by Promoting Hepatic Macrophage Polarization
复制标题
肠源性外泌体通过促进肝巨噬细胞极化诱导肠缺血/再灌注后肝损伤
DOI：
10.1007/s10753-022-01695-0
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发表时间：
2022-06
期刊：
影响因子：
5.1
通讯作者：
Cai Li
中科院分区：
文献类型：
--
作者：
Jin Zhao;Xiao-Dong Chen;Zheng-Zheng Yan;Wen-Fang Huang;Ke-Xuan Liu;Cai Li
肠缺血/再灌注（I/R）诱导的肝损伤伴有枯否细胞的极化，枯否细胞是位于肝脏的特异性巨噬细胞。然而，肠I/R后肝巨噬细胞极化的原因仍然未知。本研究在小鼠模型中探讨了肠源性外泌体是否参与肠I/R引发的肝损伤的发病机制，并探索了潜在机制。通过暂时夹闭小鼠肠系膜上动脉建立肠I/R模型。根据基于离心的方案，从经历肠I/R或假手术的小鼠肠道组织中分离外泌体。外泌体与RAW 264.7巨噬细胞共培养或静脉注射到小鼠体内。腹腔注射脂质体氯膦酸盐以清除巨噬细胞。通过流式细胞术、免疫组织化学和定量聚合酶链反应测定巨噬细胞极化。通过组织形态学以及血清天冬氨酸氨基转移酶和丙氨酸氨基转移酶水平升高来评估肝损伤。来自经历I/R的小鼠肠道的外泌体（IR - Exo）在体外促进巨噬细胞活化。静脉注射IR - Exo导致小鼠肝脏M1巨噬细胞极化并引起肝损伤。清除巨噬细胞可改善由肠I/R或注射IR - Exo引起的肝损伤。此外，抑制外泌体释放可改善肠I/R小鼠的肠道损伤、肝功能和存活率。我们的研究提供了证据，表明肠源性外泌体通过促进肝脏M1巨噬细胞极化在肠I/R后诱导肝损伤。抑制外泌体分泌可能是预防肠I/R后肝损伤的一个治疗靶点。
Liver injury induced by intestinal ischemia/reperfusion (I/R) is accompanied by the polarization of Kupffer cells, which are specialized macrophages located in the liver. However, the causes of hepatic macrophage polarization after intestinal I/R remain unknown. This study investigated whether gut-derived exosomes contribute to the pathogenesis of liver injury triggered by intestinal I/R in a murine model and explored the underlying mechanisms. Intestinal I/R models were established by temporally clamping the superior mesenteric arteries of mice. Exosomes were isolated from the intestinal tissue of mice that underwent intestinal I/R or sham surgery according to a centrifugation-based protocol. Exosomes were co-cultured with RAW 264.7 macrophages or injected intravenously in mice. Liposomal clodronate was administered intraperitoneally to deplete the macrophages. Macrophage polarization was determined by flow cytometry, immunohistochemistry, and quantitative polymerase chain reaction. Liver injury was assessed by histological morphology and increased serum aspartate aminotransferase and alanine aminotransferase levels. Exosomes from mice intestines subjected to I/R (IR-Exo) promoted macrophage activation in vitro. Intravenous injection of IR-Exo caused hepatic M1 macrophage polarization and led to liver injury in mice. Depleting macrophages ameliorated liver injury caused by intestinal I/R or the injection of IR-Exo. Furthermore, inhibiting exosome release improved intestinal injury, liver function, and survival rates of mice subjected to intestinal I/R. Our study provides evidence that gut-derived exosomes induce liver injury after intestinal I/R by promoting hepatic M1 macrophage polarization. Inhibition of exosome secretion could be a therapeutic target for preventing hepatic impairment after intestinal I/R.
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DOI：
10.4049/jimmunol.2100593
发表时间：
2022-01
期刊：
The Journal of Immunology
影响因子：
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作者：
Zhan YaQing;Ling YiHong;Deng QiWen;Qiu YuXin;Shen JianTong;Lai HanJin;Chen ZhaoRong;Huang ChanYan;Liang LiQun;Li Xiang;Wu JianFeng;Huang WenQi;Wen ShiHong
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DOI：
10.4049/jimmunol.1203170
发表时间：
2013-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
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作者：
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通讯作者：
Zhang HG
影响因子：
16
作者：
Imai T;Takahashi Y;Nishikawa M;Kato K;Morishita M;Yamashita T;Matsumoto A;Charoenviriyakul C;Takakura Y
通讯作者：
Takakura Y
DOI：
10.1016/j.bbrc.2018.12.180
发表时间：
2019-02-12
影响因子：
3.1
作者：
Chen, Yu;Sun, Huanhuan;Zhi, Fachao
通讯作者：
Zhi, Fachao
影响因子：
3.7
作者：
Zhao, Zhibo;Zhong, Li;Gong, Jianping
通讯作者：
Gong, Jianping