Chemokine Receptors, CXCR1 and CXCR2, Differentially Regulate Exosome Release in Hepatocytes.
Chemokine Receptors, CXCR1 and CXCR2, Differentially Regulate Exosome Release in Hepatocytes.
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DOI：
10.1371/journal.pone.0161443
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Lentsch AB
中科院分区：
文献类型：
--
作者：
Nojima H;Konishi T;Freeman CM;Schuster RM;Japtok L;Kleuser B;Edwards MJ;Gulbins E;Lentsch AB
外泌体是由不同细胞类型（包括肝细胞）释放的小膜囊泡，在细胞间通讯中发挥重要作用。我们先前已经证明，肝细胞来源的外泌体含有在靶肝细胞中形成鞘氨醇-1-磷酸（S1 P）的合成机制，导致缺血/再灌注（I/R）损伤后的增殖和肝再生。我们还证实趋化因子受体CXCR 1和CXCR 2调节I/R损伤后的肝脏恢复和再生。在目前的研究中，我们试图确定CXCR 1和CXCR 2对肝脏恢复和再生的调节作用是否可能通过改变肝细胞外泌体的释放而发生。我们发现肝细胞释放外来体依赖于CXCR 1和CXCR 2。与野生型对照相比，CXCR 1缺陷肝细胞产生较少的外泌体，而CXCR 2缺陷肝细胞产生更多的外泌体。在CXCR 2缺陷的肝细胞中，中性鞘磷脂酶（Nsm）和细胞内神经酰胺的活性增加。CXCR 1缺陷肝细胞Nsm活性或神经酰胺产生没有改变。有趣的是，由于缺乏中性神经酰胺酶和鞘氨醇激酶，来自CXCR 1缺陷肝细胞的外泌体对肝细胞增殖没有影响。数据表明CXCR 1和CXCR 2调节肝细胞外泌体释放。CXCR 1利用的机制仍然难以捉摸，但CXCR 2似乎调节Nsm活性和神经酰胺的产生以控制外泌体释放。CXCR 1是将酶包装到介导其肝细胞增殖作用的外泌体中所必需的。
Exosomes are small membrane vesicles released by different cell types, including hepatocytes, that play important roles in intercellular communication. We have previously demonstrated that hepatocyte-derived exosomes contain the synthetic machinery to form sphingosine-1-phosphate (S1P) in target hepatocytes resulting in proliferation and liver regeneration after ischemia/reperfusion (I/R) injury. We also demonstrated that the chemokine receptors, CXCR1 and CXCR2, regulate liver recovery and regeneration after I/R injury. In the current study, we sought to determine if the regulatory effects of CXCR1 and CXCR2 on liver recovery and regeneration might occur via altered release of hepatocyte exosomes. We found that hepatocyte release of exosomes was dependent upon CXCR1 and CXCR2. CXCR1-deficient hepatocytes produced fewer exosomes, whereas CXCR2-deficient hepatocytes produced more exosomes compared to their wild-type controls. In CXCR2-deficient hepatocytes, there was increased activity of neutral sphingomyelinase (Nsm) and intracellular ceramide. CXCR1-deficient hepatocytes had no alterations in Nsm activity or ceramide production. Interestingly, exosomes from CXCR1-deficient hepatocytes had no effect on hepatocyte proliferation, due to a lack of neutral ceramidase and sphingosine kinase. The data demonstrate that CXCR1 and CXCR2 regulate hepatocyte exosome release. The mechanism utilized by CXCR1 remains elusive, but CXCR2 appears to modulate Nsm activity and resultant production of ceramide to control exosome release. CXCR1 is required for packaging of enzymes into exosomes that mediate their hepatocyte proliferative effect.