Identification of a novel interaction between corticotropin releasing hormone (Crh) and macroautophagy.
Identification of a novel interaction between corticotropin releasing hormone (Crh) and macroautophagy.
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DOI：
10.1038/srep23342
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发表时间：
2016-03-18
影响因子：
4.6
通讯作者：
Karalis KP
中科院分区：
文献类型：
--
作者：
Giannogonas P;Apostolou A;Manousopoulou A;Theocharis S;Macari SA;Psarras S;Garbis SD;Pothoulakis C;Karalis KP
在炎症性肠病（IBD）中，上皮屏障受损的恢复有助于疾病的严重程度。由于IBD发病机制的复杂性，多种因素已涉及其进展。在这项研究中，我们报道了肠道中巨噬和促肾上腺皮质激素释放激素（Crh）之间的功能相互作用。为此，我们使用具有自噬药理抑制作用的Crh - / -或野生型（wt）的DSS结肠炎模型。我们发现Crh−/−小鼠肠道中持续的基础自噬，这种自噬在DSS给药过程中持续存在。自噬抑制导致Crh - / -小鼠的部分拯救，同时增加了wt肠道中Crh的表达。同样，Crh缺乏与基线自噬的持续激活有关。体外氨基酸剥夺和脂多糖诱导的自噬模型证实了体内的研究结果。我们的研究结果表明，Crh在肠上皮中的新作用涉及自噬的调节，同时表明两种途径的互补作用。这些数据提示了一种有趣的可能性，即在肠道中靶向Crh刺激可能提供一种新的治疗方法来支持上皮屏障的完整性并保护慢性结肠炎。
In inflammatory bowel disease (IBD), compromised restitution of the epithelial barrier contributes to disease severity. Owing to the complexity in the pathogenesis of IBD, a variety of factors have been implicated in its progress. In this study, we report a functional interaction between macroautophagy and Corticotropin Releasing Hormone (Crh) in the gut. For this purpose we used DSS colitis model on Crh −/− or wild-type (wt) with pharmacological inhibition of autophagy. We uncovered sustained basal autophagy in the gut of Crh −/− mice, which persisted over the course of DSS administration. Autophagy inhibition resulted in partial rescue of Crh −/− mice, while it increased the expression of Crh in the wt gut. Similarly, Crh deficiency was associated with sustained activation of base line autophagy. In vitro models of amino acid deprivation- and LPS-induced autophagy confirmed the in vivo findings. Our results indicate a novel role for Crh in the intestinal epithelium that involves regulation of autophagy, while suggesting the complementary action of the two pathways. These data suggest the intriguing possibility that targeting Crh stimulation in the intestine may provide a novel therapeutic approach to support the integrity of the epithelial barrier and to protect from chronic colitis.