The neuroimmune guidance cue netrin-1 controls resolution programs and promotes liver regeneration
The neuroimmune guidance cue netrin-1 controls resolution programs and promotes liver regeneration
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DOI：
10.1002/hep.28347
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发表时间：
2016-05-01
期刊：
影响因子：
13.5
通讯作者：
Mirakaj, Valbona
中科院分区：
文献类型：
--
作者：
Schlegel, Martin;Koehler, David;Mirakaj, Valbona
肝脏缺血再灌注(I/R)是肝移植、失血性休克或肝切除的主要不良反应。最近，轴突导向线索netrin-1的抗炎作用被报道。在这里，我们证明Netrin-1也影响炎症的消退，并促进肝脏I/R损伤时的肝修复和再生。在最初的研究中，我们研究了I/R损伤后小鼠肝组织中Netrin-1及其受体的诱导。对部分遗传性Netrin-1缺乏(Ntn1(+/-))的小鼠或外源性Netrin-1处理的野生型C57BL/6小鼠进行肝脏I/R损伤，以检测Netrin-1的内源性和治疗作用。这些研究得到了以下研究的证实：血管内白细胞流动的特征，中性粒细胞(PMN)的凋亡清除，特殊促分解脂介质(SPM)的产生，有助于消退炎症的特定生长因子的产生，以及肝脏修复。肝脏I/R与小鼠肝组织中netrin-1转录本和蛋白的显著减少有关。随后对Netrin-1缺陷小鼠的研究显示，在减少PMN渗透、促炎细胞因子水平和肝脏特异性损伤酶方面效果较差。相反，外源性netrin-1治疗的小鼠表现出增强的肝脏保护和修复，减少中性粒细胞流入损伤部位，减少促炎介质，增加凋亡的PMN的吞噬，并刺激局部内源性SPM的生物合成和特定生长因子的产生。最后，遗传学研究表明，A2B腺苷受体在Netrin-1介导的肝I/R损伤保护中起作用。结论：本研究表明Netrin-1在肝脏保护中的作用以及它对组织内稳态和再生的贡献是以前未知的。(《肝病》2016；63：1689-1705)
Hepatic ischemia/reperfusion (I/R) is a major adverse reaction to liver transplantation, hemorrhagic shock, or resection. Recently, the anti-inflammatory properties of the axonal guidance cue netrin-1 were reported. Here, we demonstrate that netrin-1 also impacts the resolution of inflammation and promotes hepatic repair and regeneration during liver I/R injury. In initial studies, we investigated the induction of netrin-1 and its receptors in murine liver tissues after I/R injury. Hepatic I/R injury was performed in mice with a partial genetic netrin-1 deficiency (Ntn1(+/-)) or wild-type C57BL/6 treated with exogenous netrin-1 to examine the endogenous and therapeutically administered impact of netrin-1. These investigations were corroborated by studies determining the characteristics of intravascular leukocyte flow, clearance of apoptotic neutrophils (polymorphonuclear cells [PMNs]), production of specialized proresolving lipid mediators (SPMs), generation of specific growth factors contributing to the resolution of inflammation, and liver repair. Hepatic I/R was associated with a significant reduction of netrin-1 transcript and protein in murine liver tissue. Subsequent studies in netrin-1-deficient mice revealed lower efficacies in reducing PMN infiltration, proinflammatory cytokine levels, and hepatic-specific injury enzymes. Conversely, mice treated with exogenous netrin-1 exhibited increased liver protection and repair, reducing neutrophil influx into the injury site, decreasing proinflammatory mediators, increasing efferocytosis of apoptotic PMNs, and stimulating local endogenous biosynthesis of SPMs and the generation of specific growth factors. Finally, genetic studies implicated the A2B adenosine receptor in netrin-1-mediated protection during hepatic I/R injury. Conclusion: The present study indicates a previously unrecognized role for netrin-1 in liver protection and its contribution to tissue homeostasis and regeneration. (Hepatology 2016;63:1689-1705)