Jejunal epithelial barrier disruption triggered by reactive oxygen species in early SIV infected rhesus macaques
Jejunal epithelial barrier disruption triggered by reactive oxygen species in early SIV infected rhesus macaques
复制标题
早期 SIV 感染恒河猴中活性氧引发空肠上皮屏障破坏
DOI：
10.1016/j.freeradbiomed.2021.10.026
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发表时间：
2021
影响因子：
7.4
通讯作者：
Zheng Yong-Tang
中科院分区：
文献类型：
--
作者：
Wang Xue-Hui;Song Tian-Zhang;Zheng Hong-Yi;Li Yi-Hui;Zheng Yong-Tang
在人类免疫缺陷病毒(HIV)和猴免疫缺陷病毒(SIV)感染的急性期，肠上皮屏障的破坏发生在黏膜免疫功能障碍之前。然而，目前，SIV感染早期胃肠完整性受损的原因仍不清楚。在本研究中，我们研究了SIV感染对上皮屏障完整性的影响，并探讨了氧化应激对急性SIVmac239感染的中国猕猴(Macaca Mulatta)早期上皮细胞DNA损伤和凋亡的影响。结果表明，SIV感染后14d血浆中反映小肠屏障功能障碍的敏感分子标志物--肠道脂肪酸结合蛋白(IFABP)显著升高。SIV感染导致上皮细胞紧密连接蛋白claudin-1、claudin-3和zonula occludens(ZO)-1的表达显著降低，活化形式的caspase-3水平显著升高。RNA测序(RNA-seq)分析表明，SIV感染前后空肠差异表达基因在细胞氧化还原动态平衡、氧化还原酶活性和线粒体途径中得到丰富。事实上，在SIV感染的空肠中，观察到SIV介导的上皮和巨噬细胞中活性氧物种(ROS)的增加，以及过氧化氢(H_2O_2)的增加和谷胱甘肽(GSH)/谷胱甘肽二硫化物(GSSG)抗氧化防御的降低。此外，线粒体功能障碍和DNA氧化损伤的积累导致肠上皮细胞衰老相关β-半乳糖苷酶(SA-β-GAL)增加和早期凋亡。此外，抗氧化剂N-乙酰半胱氨酸(NAC)可挽救HIV-1 Tat蛋白诱导的HT-29癌细胞上皮单层断裂。这些结果表明，空肠上皮细胞线粒体功能障碍和氧化应激是SIV感染早期恒河猴肠道上皮屏障破坏的主要原因。
Intestinal epithelial barrier destruction occurs earlier than mucosal immune dysfunction in the acute stage of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections. At present, however, the cause of compromised gastrointestinal integrity in early SIV infection remains unknown. In the current study, we investigated the effects of SIV infection on epithelial barrier integrity and explored oxidative stress-mediated DNA damage and apoptosis in epithelial cells from early acute SIVmac239-infected Chinese rhesus macaques (Macaca mulatta). Results showed that the sensitive molecular marker of small intestinal barrier dysfunction, i.e., intestinal fatty acid-binding protein (IFABP), was significantly increased in plasma at 14 days post-SIV infection. SIV infection induced a profound decrease in the expression of tight junction proteins, including claudin-1, claudin-3, and zonula occludens (ZO)-1, as well as a significant increase in the active form of caspase-3 level in epithelial cells. RNA sequencing (RNA-seq) analysis suggested that differentially expressed genes between pre- and post-SIV-infected jejuna were enriched in pathways involved in cell redox homeostasis, oxidoreductase activity, and mitochondria. Indeed, a SIV-mediated increase in reactive oxygen species (ROS) in the epithelium and macrophages, as well as an increase in hydrogen peroxide (H2O2) and decrease in glutathione (GSH)/glutathione disulfide (GSSG) antioxidant defense, were observed in SIV-infected jejuna. In addition, the accumulation of mitochondrial dysfunction and DNA oxidative damage led to an increase in senescence-associated β-galactosidase (SA-β-gal) and early apoptosis in intestinal epithelial cells. Furthermore, HIV-1 Tat protein-induced epithelial monolayer disruption in HT-29 cells was rescued by antioxidantN-acetylcysteine (NAC). These results indicate that mitochondrial dysfunction and oxidative stress in jejunal epithelial cells are primary contributors to gut epithelial barrier disruption in early SIV-infected rhesus macaques.