Loss of L-selectin-guided CD8(+) , but not CD4(+) , cells protects against ischemia reperfusion injury in a steatotic liver.
Loss of L-selectin-guided CD8(+) , but not CD4(+) , cells protects against ischemia reperfusion injury in a steatotic liver.
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DOI：
10.1002/hep.29276
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Gupta NA
中科院分区：
文献类型：
--
作者：
Kolachala VL;Palle S;Shen M;Feng A;Shayakhmetov D;Gupta NA
当暴露于缺血-再灌注损伤时，脂肪变性肝的反应是肝细胞损伤增加。越来越多的证据支持免疫细胞在正常（瘦）状态下作为这种损伤的关键介质的作用，但关于它们在脂肪肝中的作用的数据实际上是不存在的。当前研究的目的是描述特定表型的T细胞和粘附分子在脂肪变性肝损伤中加剧细胞死亡的贡献。对高脂饮食（HFD）小鼠缺血再灌注损伤（IRI）后肝淋巴细胞进行RNA测序和T细胞标记物测定。CD8 - / -和CD4 - / -小鼠与CD8和l -选择素抗体处理的小鼠一起饲喂HFD， IRI后通过组织学、碘化丙啶注射和ALT评估肝细胞损伤。RNA测序显示了脂肪变性肝细胞与瘦肝细胞的显著差异基因谱。损伤后HFD肝组织坏死、CD8+细胞浸润、ALT及促炎因子增加。肝脏淋巴细胞CD8+/CD62L+（l -选择素）细胞增加。CD8−/−小鼠和CD8缺失的C57BL/6小鼠显示出对损伤的显著保护作用，这在CD4−/−小鼠中未见。l -选择素阻断也对IRI有显著的肝保护作用。在HFD喂养的IRI小鼠中，L选择素配体MECA-79升高。阻断CD8和l -选择素而非CD4可改善肝细胞损伤，证实CD8+细胞是脂肪变性肝损伤的关键驱动因素。这代表了脂肪变性肝损伤的一个新的治疗靶点，强调了开发针对脂肪变性肝的治疗方法的重要性。
Steatotic liver responds with increased hepatocellular injury when exposed to an ischemic-reperfusion insult. Increasing evidence supports the role of immune cells as key mediators of this injury in a normal (lean) state, but data about their role in a steatotic liver are practically non-existent. The objective of the current study was to delineate contribution of specific phenotypes of T cells and adhesion molecules in exacerbated cell death in steatotic liver injury. RNA sequencing was performed on isolated steatotic primary hepatocytes and T cell markers were assessed in hepatic lymphocytes after ischemia reperfusion injury (IRI) in high fat diet (HFD) fed mice. CD8−/− and CD4−/− mice along with CD8 and L-selectin antibody treated mice were fed on a HFD and hepatocellular injury was assessed by histology, propidium iodide injection and ALT after IRI. RNA sequencing demonstrated a strikingly differential gene profile in steatotic hepatocytes vs. lean hepatocytes. After injury, the HFD liver showed increased necrosis, infiltrating CD8+ cells, ALT and proinflammatory cytokines. Hepatic lymphocytes demonstrated increased CD8+/CD62L+(L-selectin) cells in HFD fed mice after IRI. CD8−/− mice and CD8 depleted C57BL/6 mice, demonstrated significant protection from injury, which was not seen in CD4−/− mice. L-selectin blockade also demonstrated significant hepatoprotection from IRI. L selectin ligand MECA-79 was increased in HFD fed mice undergoing IRI. Blockade of CD8 and L-selectin but not CD4, ameliorated hepatocellular injury, confirming that CD8+ cells are critical drivers of injury in a steatotic liver. This represents a novel therapeutic target in steatotic liver injury, underlining the importance of development of therapies specific to a steatotic liver.
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DOI：
10.1097/mpg.0000000000001008
发表时间：
2016-03
影响因子：
2.9
作者：
Kolachala VL;Jiang R;Abramowsky CR;Gupta NA
通讯作者：
Gupta NA
影响因子：
24.5
作者：
Feldstein AE;Charatcharoenwitthaya P;Treeprasertsuk S;Benson JT;Enders FB;Angulo P
通讯作者：
Angulo P
影响因子：
64.8
作者：
GALLATIN, WM;WEISSMAN, IL;BUTCHER, EC
通讯作者：
BUTCHER, EC
DOI：
10.1152/ajpgi.00210.2014
发表时间：
2014-12-01
影响因子：
4.5
作者：
Gupta, Nitika A.;Kolachala, Vasantha L.;Kirk, Allan D.
通讯作者：
Kirk, Allan D.
影响因子：
2.2
作者：
Martinez-Mier, G;Toledo-Pereyra, LH;Ward, PA
通讯作者：
Ward, PA