Cross-activating invariant NKT cells and kupffer cells suppress cholestatic liver injury in a mouse model of biliary obstruction.
Cross-activating invariant NKT cells and kupffer cells suppress cholestatic liver injury in a mouse model of biliary obstruction.
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跨激活不变的NKT细胞和库普弗细胞在胆道阻塞的小鼠模型中抑制胆汁淤积性肝损伤。
DOI：
10.1371/journal.pone.0079702
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Gregory SH
中科院分区：
文献类型：
--
作者：
Duwaerts CC;Sun EP;Cheng CW;van Rooijen N;Gregory SH
库普弗细胞和不变的自然杀伤T（iNKT）细胞抑制胆道梗阻小鼠模型中嗜中性粒细胞依赖性肝损伤。我们假设这些作用是相互依赖的，并且需要iNKT细胞-枯否细胞交叉激活。在胆管结扎（BDL）前3天，向雌性、野生型和iNKT细胞缺陷型C57 B1/6小鼠注射磁珠，以促进随后的库普弗细胞分离。在BDL后第三天，对动物实施安乐死并解剖肝脏。对坏死进行评分;分离枯否细胞，并检测细胞表面标志物表达（流式细胞术）、mRNA表达（qtPCR）、一氧化氮（NO.）测定蛋白质产生（Griess反应）和蛋白质分泌（细胞计数珠阵列或ELISA）。为了解决NO在抑制中性粒细胞积聚中的潜在作用，一组WT小鼠在BDL之前接受1400 W，一种特异性诱导型一氧化氮合酶（iNOS）抑制剂。为了阐明库普弗细胞-iNKT细胞交叉活化的潜在机制，在BDL之前对WT动物施用抗IFN-γ或抗淋巴细胞功能相关抗原（LFA）-1抗体。与WT细胞相比，从BDL iNKT细胞缺陷小鼠获得的Kupffer细胞表达较低的iNOS mRNA水平，产生较少的NO，分泌更多的中性粒细胞趋化因子。iNOS抑制和IFN-γ中和均增加BDL WT小鼠肝脏中的中性粒细胞积聚。抗LFA-1预处理减少了这些相同动物中的iNKT细胞积累。这些数据表明iNKT细胞和枯否细胞的LFA-1依赖性交叉激活抑制了中性粒细胞积聚和胆汁淤积性肝损伤。
Both Kupffer cells and invariant natural killer T (iNKT) cells suppress neutrophil-dependent liver injury in a mouse model of biliary obstruction. We hypothesize that these roles are interdependent and require iNKT cell-Kupffer cell cross-activation. Female, wild-type and iNKT cell-deficient C57Bl/6 mice were injected with magnetic beads 3 days prior to bile duct ligation (BDL) in order to facilitate subsequent Kupffer cell isolation. On day three post-BDL, the animals were euthanized and the livers dissected. Necrosis was scored; Kupffer cells were isolated and cell surface marker expression (flow cytometry), mRNA expression (qtPCR), nitric oxide (NO.) production (Griess reaction), and protein secretion (cytometric bead-array or ELISAs) were determined. To address the potential role of NO. in suppressing neutrophil accumulation, a group of WT mice received 1400W, a specific inducible nitric oxide synthase (iNOS) inhibitor, prior to BDL. To clarify the mechanisms underlying Kupffer cell-iNKT cell cross-activation, WT animals were administered anti-IFN-γ or anti-lymphocyte function-associated antigen (LFA)-1 antibody prior to BDL. Compared to their WT counterparts, Kupffer cells obtained from BDL iNKT cell-deficient mice expressed lower iNOS mRNA levels, produced less NO., and secreted more neutrophil chemoattractants. Both iNOS inhibition and IFN-γ neutralization increased neutrophil accumulation in the livers of BDL WT mice. Anti-LFA-1 pre-treatment reduced iNKT cell accumulation in these same animals. These data indicate that the LFA-1-dependent cross-activation of iNKT cells and Kupffer cells inhibits neutrophil accumulation and cholestatic liver injury.
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