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Abstract：
Previous studies have demonstrated that natural killer (NK) cells migrated into the liver from peripheral organs and exerted cytotoxic effects on hepatocytes in virus-induced liver failure.
This study aimed to investigate the potential therapeutic role of chemokine receptors in the migration of NK cells in a murine hepatitis virus strain 3 (MHV-3)-induced fulminant hepatic failure (MHV-3-FHF) model and its mechanism.
By gene array analysis, chemokine (C-C motif) receptor 5 (CCR5) was found to have remarkably elevated expression levels in hepatic NK cells after MHV-3 infection. The number of hepatic CCR5+ conventional NK (cNK) cells increased and peaked at 48 h after MHV-3 infection, while the number of hepatic resident NK (rNK) cells steadily declined. Moreover, the expression of CCR5-related chemokines, including macrophage inflammatory protein (MIP)-1α, MIP-1β and regulated on activation, normal T-cell expressed and secreted (RANTES) was significantly upregulated in MHV-3-infected hepatocytes. In an in vitro Transwell migration assay, CCR5-blocked splenic cNK cells showed decreased migration towards MHV-3-infected hepatocytes, and inhibition of MIP-1β or RANTES but not MIP-1α decreased cNK cell migration. Moreover, CCR5 knockout (KO) mice displayed reduced infiltration of hepatic cNK cells after MHV-3 infection, accompanied by attenuated liver injury and improved mouse survival time. Adoptive transfer of cNK cells from wild-type mice into CCR5 KO mice resulted in the abundant accumulation of hepatic cNK cells and aggravated liver injury. Moreover, pharmacological inhibition of CCR5 by maraviroc reduced cNK cell infiltration in the liver and liver injury in the MHV-3-FHF model.
The CCR5-MIP-1β/RANTES axis played a critical role in the recruitment of cNK cells to the liver during MHV-3-induced liver injury. Targeted inhibition of CCR5 provides a therapeutic approach to ameliorate liver damage during virus-induced acute liver injury.
This study aimed to investigate the potential therapeutic role of chemokine receptors in the migration of NK cells in a murine hepatitis virus strain 3 (MHV-3)-induced fulminant hepatic failure (MHV-3-FHF) model and its mechanism.
By gene array analysis, chemokine (C-C motif) receptor 5 (CCR5) was found to have remarkably elevated expression levels in hepatic NK cells after MHV-3 infection. The number of hepatic CCR5+ conventional NK (cNK) cells increased and peaked at 48 h after MHV-3 infection, while the number of hepatic resident NK (rNK) cells steadily declined. Moreover, the expression of CCR5-related chemokines, including macrophage inflammatory protein (MIP)-1α, MIP-1β and regulated on activation, normal T-cell expressed and secreted (RANTES) was significantly upregulated in MHV-3-infected hepatocytes. In an in vitro Transwell migration assay, CCR5-blocked splenic cNK cells showed decreased migration towards MHV-3-infected hepatocytes, and inhibition of MIP-1β or RANTES but not MIP-1α decreased cNK cell migration. Moreover, CCR5 knockout (KO) mice displayed reduced infiltration of hepatic cNK cells after MHV-3 infection, accompanied by attenuated liver injury and improved mouse survival time. Adoptive transfer of cNK cells from wild-type mice into CCR5 KO mice resulted in the abundant accumulation of hepatic cNK cells and aggravated liver injury. Moreover, pharmacological inhibition of CCR5 by maraviroc reduced cNK cell infiltration in the liver and liver injury in the MHV-3-FHF model.
The CCR5-MIP-1β/RANTES axis played a critical role in the recruitment of cNK cells to the liver during MHV-3-induced liver injury. Targeted inhibition of CCR5 provides a therapeutic approach to ameliorate liver damage during virus-induced acute liver injury.
摘要：
背景：先前的研究表明，自然杀伤（NK）细胞从外周器官迁移到肝脏中，并在病毒诱导的肝衰竭中对肝细胞产生细胞毒性作用。
目的：本研究旨在探讨趋化因子受体在小鼠肝炎病毒3株（MHV-3）诱导的暴发性肝衰竭（MHV-3-FHF）模型中NK细胞迁移中的潜在治疗作用及其机制。
结果：通过基因阵列分析，发现MHV-3感染后，趋化因子（C-C基序）受体5（CCR5）在肝NK细胞中的表达水平显着升高。在MHV-3感染后48h，肝脏CCR5+常规NK（cNK）细胞数量增加并达到峰值，而肝脏常驻NK（rNK）细胞的数量稳步下降。此外，CCR5相关趋化因子的表达，包括巨噬细胞炎性蛋白（MIP）-1α，MIP-1β并在激活时受到调节，正常T细胞表达和分泌（RANTES）在MHV-3感染的肝细胞中显著上调。在体外Transwell迁移试验中，CCR5阻断的脾cNK细胞显示向MHV-3感染的肝细胞迁移减少，抑制MIP-1β或RANTES而不是MIP-1α会降低cNK细胞的迁移。此外，CCR5基因敲除(KO)小鼠显示MHV-3感染后肝脏cNK细胞浸润减少,伴随着减轻肝损伤和改善小鼠生存时间。将野生型小鼠的cNK细胞过继转移到CCR5KO小鼠中，导致肝脏cNK细胞大量积累并加重肝损伤。此外，在MHV-3-FHF模型中，maraviroc对CCR5的药理学抑制减少了肝脏中cNK细胞的浸润和肝损伤。
结论：在MHV-3诱导的肝损伤期间，CCR5-MIP-1β/RANTES轴在cNK细胞募集到肝脏中起关键作用。CCR5的靶向抑制提供了在病毒诱导的急性肝损伤期间改善肝损伤的治疗方法。
目的：本研究旨在探讨趋化因子受体在小鼠肝炎病毒3株（MHV-3）诱导的暴发性肝衰竭（MHV-3-FHF）模型中NK细胞迁移中的潜在治疗作用及其机制。
结果：通过基因阵列分析，发现MHV-3感染后，趋化因子（C-C基序）受体5（CCR5）在肝NK细胞中的表达水平显着升高。在MHV-3感染后48h，肝脏CCR5+常规NK（cNK）细胞数量增加并达到峰值，而肝脏常驻NK（rNK）细胞的数量稳步下降。此外，CCR5相关趋化因子的表达，包括巨噬细胞炎性蛋白（MIP）-1α，MIP-1β并在激活时受到调节，正常T细胞表达和分泌（RANTES）在MHV-3感染的肝细胞中显著上调。在体外Transwell迁移试验中，CCR5阻断的脾cNK细胞显示向MHV-3感染的肝细胞迁移减少，抑制MIP-1β或RANTES而不是MIP-1α会降低cNK细胞的迁移。此外，CCR5基因敲除(KO)小鼠显示MHV-3感染后肝脏cNK细胞浸润减少,伴随着减轻肝损伤和改善小鼠生存时间。将野生型小鼠的cNK细胞过继转移到CCR5KO小鼠中，导致肝脏cNK细胞大量积累并加重肝损伤。此外，在MHV-3-FHF模型中，maraviroc对CCR5的药理学抑制减少了肝脏中cNK细胞的浸润和肝损伤。
结论：在MHV-3诱导的肝损伤期间，CCR5-MIP-1β/RANTES轴在cNK细胞募集到肝脏中起关键作用。CCR5的靶向抑制提供了在病毒诱导的急性肝损伤期间改善肝损伤的治疗方法。
