新型巨噬细胞移动抑制因子在乙醇喂养小鼠未折叠蛋白反应上游调控中的作用。
Novel Role of Macrophage Migration Inhibitory Factor in Upstream Control of the Unfolded Protein Response After Ethanol Feeding in Mice.
机构信息
Department of Inflammation and Immunity, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio.
Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio.
出版信息
Alcohol Clin Exp Res. 2019 Jul;43(7):1439-1451. doi: 10.1111/acer.14065. Epub 2019 May 14.
BACKGROUND
Macrophage migration inhibitory factor (MIF), a pluripotent immune regulator, is an emerging mediator in alcohol-related liver disease (ALD). MIF is associated with ALD progression through its chemokine- and cytokine-like activities.
METHODS
Mechanistic studies into the role of MIF in ethanol (EtOH)-induced liver injury were performed in Mif mice and in C57BL/6J mice treated with a small-molecule MIF antagonist, MIF098, after Gao-Binge (acute-on-chronic) EtOH feeding, an EtOH feeding protocol associated with hepatic neutrophilia and induction of the unfolded protein response (UPR).
RESULTS
The MIF axis, for example, MIF and MIF receptors invariant polypeptide of major histocompatibility complex, class II antigen-associated (CD74), CXCR2, CXCR4, and CXCR7, was enhanced in the livers of alcoholic hepatitis (AH) patients as compared to healthy controls. Mif mice were protected from hepatocellular injury after Gao-Binge feeding, independent of neutrophilia and inflammation, but were associated with the UPR. Interestingly, the UPR signature in AH patients and in mice following Gao-Binge feeding was biased toward cell death with increased expression of pro-cell death CCAAT-enhancer-binding protein homologous protein (CHOP) and decreased prosurvival GRP78. The UPR and liver injury 6 hours after binge were prevented both in Mif mice and in MIF098-treated mice. However, both MIF interventions led to increased liver injury and exacerbated the hepatic UPR 9 hours after binge. Induction of upstream UPR signaling and expression of CHOP protein by thapsigargin in alpha mouse liver 12 hepatocytes were blunted by coexposure to MIF098, directly connecting MIF to UPR in hepatocytes.
CONCLUSIONS
The current study revealed that, in addition to its cytokine/chemokine functions, MIF is an upstream regulator of UPR in response to EtOH feeding in mice. Importantly, both MIF and UPR can either protect or contribute to liver injury, dependent upon the stage or severity of EtOH-induced liver injury.
背景
巨噬细胞移动抑制因子（MIF）是一种多功能免疫调节剂，是酒精相关肝病（ALD）中的新兴介质。MIF 通过其趋化因子和细胞因子样活性与 ALD 的进展相关。
方法
在 Mif 小鼠和用小分子 MIF 拮抗剂 MIF098 处理的 C57BL/6J 小鼠中进行了 MIF 在乙醇（EtOH）诱导的肝损伤中的作用的机制研究，这些小鼠接受了 Gao-Binge（急性-慢性）EtOH 喂养，这是一种与肝中性粒细胞增多和未折叠蛋白反应（UPR）诱导相关的 EtOH 喂养方案。
结果
例如，与健康对照相比，酒精性肝炎（AH）患者的肝脏中 MIF 轴（例如 MIF 和 MHC II 抗原相关的不变多肽的 MIF 受体（CD74）、CXCR2、CXCR4 和 CXCR7）增强。Mif 小鼠在 Gao-Binge 喂养后免受肝细胞损伤，与中性粒细胞增多和炎症无关，但与 UPR 相关。有趣的是，AH 患者和 Gao-Binge 喂养后小鼠的 UPR 特征偏向于细胞死亡，表现为促细胞死亡 CCAAT 增强子结合蛋白同源蛋白（CHOP）表达增加和促生存 GRP78 减少。在 Mif 小鼠和 MIF098 治疗的小鼠中，6 小时 binge 后的 UPR 和肝损伤均得到预防。然而，两种 MIF 干预都导致肝损伤增加，并在 binge 后 9 小时加剧肝 UPR。在 alpha 小鼠肝 12 细胞中，用 thapsigargin 诱导的 UPR 上游信号转导和 CHOP 蛋白的表达被 MIF098 共同暴露所抑制，直接将 MIF 与肝细胞中的 UPR 联系起来。
结论
本研究揭示了，除了其细胞因子/趋化因子功能外，MIF 还是小鼠对 EtOH 喂养反应中 UPR 的上游调节剂。重要的是，MIF 和 UPR 都可以保护或导致肝损伤，这取决于 EtOH 诱导的肝损伤的阶段或严重程度。
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