TNF-α-dependent Regulation of Acute Pancreatitis Severity by Ly-6Chi Monocytes in Mice
TNF-α-dependent Regulation of Acute Pancreatitis Severity by Ly-6Chi Monocytes in Mice
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DOI：
10.1074/jbc.m111.218388
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发表时间：
2011-04-15
影响因子：
4.8
通讯作者：
Steer, Michael L.
中科院分区：
文献类型：
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作者：
Perides, George;Weiss, Eric R.;Steer, Michael L.
单核细胞/巨噬细胞在胰腺炎调控中的作用及其作用机制尚不清楚。为了解决这些问题，我们采用了基因改变的小鼠品系，这些小鼠品系要么表达与CD 11b启动子偶联的人白喉毒素受体（DTR），要么具有TNF-α的整体缺失。通过对CD 11b-DTR小鼠给予白喉毒素（DT）实现单核细胞/巨噬细胞的靶向条件性耗竭。我们发现，在没有DT给药的情况下，胰腺炎与胰腺中Ly-6C（hi）单核细胞/巨噬细胞含量的增加有关，但这种反应可通过预先给CD 11b-DTR小鼠DT来预防。DT给药还减少了两种不同的急性胰腺炎实验模型（促分泌素诱导的模型和牛磺胆酸钠逆行胰管输注引起的模型）中的胰腺水肿和腺泡细胞损伤/坏死。在促分泌素诱导的模型中，通过过继转移从非DT处理的CD 11b-DTR小鼠收获的纯化Ly-6C（hi）单核细胞或转移从TNF-α（+/+）供体小鼠收获的纯化Ly-6C（hi）单核细胞，DT诱导的胰腺炎严重程度降低被逆转，但转移从TNF-α（-/-）供体收获的Ly-6C（hi）单核细胞不能逆转。我们的研究表明，Ly-6C（hi）单核细胞亚群通过促进胰腺水肿和腺泡细胞损伤/坏死来调节胰腺炎的严重程度，并且这种现象依赖于这些细胞表达TNF-α。他们认为靶向Ly-6C（hi）单核细胞和/或Ly-6C（hi）单核细胞表达TNF-α的疗法可能证明对预防或治疗急性胰腺炎有益。
The roles of monocytes/macrophages and their mechanisms of action in the regulation of pancreatitis are poorly understood. To address these issues, we have employed genetically altered mouse strains that either express the human diphtheria toxin receptor (DTR) coupled to the CD11b promoter or have global deletion of TNF-alpha. Targeted, conditional depletion of monocytes/macrophages was achieved by administration of diphtheria toxin (DT) to CD11b-DTR mice. We show that in the absence of DT administration, pancreatitis is associated with an increase in pancreatic content of Ly-6C(hi) monocytes/macrophages but that this response is prevented by prior administration of DT to CD11b-DTR mice. DT administration also reduces pancreatic edema and acinar cell injury/necrosis in two dissimilar experimental models of acute pancreatitis (a secretagogue-induced model and a model elicited by retrograde pancreatic duct infusion of sodium taurocholate). In the secretagogue-elicited model, the DT-induced decrease in pancreatitis severity is reversed by adoptive transfer of purified Ly-6C(hi) monocytes harvested from non-DT-treated CD11b-DTR mice or by the transfer of purified Ly-6C(hi) monocytes harvested from TNF-alpha(+/+) donor mice, but it is not reversed by the transfer of Ly-6C(hi) monocytes harvested from TNF-alpha(-/-) donors. Our studies indicate that the Ly-6C(hi) monocyte subset regulates the severity of pancreatitis by promoting pancreatic edema and acinar cell injury/necrosis and that this phenomenon is dependent upon the expression of TNF-alpha by those cells. They suggest that therapies targeting Ly-6C(hi) monocytes and/or TNF-alpha expression by Ly-6C(hi) monocytes might prove beneficial in the prevention or treatment of acute pancreatitis.