Alpha7 Nicotinic Acetylcholine Receptor Alleviates Inflammatory Bowel Disease Through Induction of AMPK-mTOR-p70S6K-Mediated Autophagy
Alpha7 Nicotinic Acetylcholine Receptor Alleviates Inflammatory Bowel Disease Through Induction of AMPK-mTOR-p70S6K-Mediated Autophagy
复制标题
Alpha7 烟碱乙酰胆碱受体通过诱导 AMPK-mTOR-p70S6K 介导的自噬减轻炎症性肠病
DOI：
10.1007/s10753-019-01027-9
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发表时间：
2019-10-01
期刊：
影响因子：
5.1
通讯作者：
Wu, Kai
中科院分区：
文献类型：
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作者：
Shao, Bo-Zong;Wang, Shu-Ling;Wu, Kai
α 7烟碱乙酰胆碱受体（α 7 nAChR）在多种疾病中通过抑制炎症而发挥保护作用。在这里，我们研究了α 7 nAChR在炎症性肠病（IBD）中的作用，α 7 nAChR缺陷小鼠（α 7 nAChR（-/-））和野生型小鼠（α 7 nAChR（+/+））。用3%葡聚糖硫酸钠（DSS）建立IBD小鼠模型，并以脂多糖（LPS）/DSS作为炎症应激源刺激小鼠骨髓源性巨噬细胞（BMDM）。采用HE染色、酶联免疫吸附试验（ELISA）和实时荧光定量PCR检测炎症活化水平。Western blot检测自噬相关蛋白的表达水平。应用透射电镜和mRFP-GFP-LC 3质粒检测自噬水平。我们证明，在DSS诱导的结肠炎模型中，α 7 nAChR的缺乏对IBD的严重程度和炎症反应产生不利影响。这些作用是通过自噬功能障碍引起的。α 7 nAChR缺乏减弱了自噬诱导剂在IBD小鼠和LPS/DSS攻击的BMDM中的保护和抗炎作用。通过抑制腺苷5 '-一磷酸（AMP）激活的蛋白激酶（AMPK）介导的信号传导，减弱了激活α 7 nAChR的抑制作用。总之，α 7 nAChR通过诱导AMPK-哺乳动物雷帕霉素靶蛋白兔（mTOR）-p70核糖体蛋白S6激酶（p70 S6 K）介导的自噬而有助于减轻IBD，从而为IBD的治疗提供了新的靶点。
Alpha7 nicotinic acetylcholine receptor (alpha 7nAChR) has been reported to be protective in several kinds of disorders through inflammatory suppression. Here, we investigated the role of alpha 7nAChR in inflammatory bowel disease (IBD) on alpha 7nAChR deficient mice (alpha 7nAChR(-/-)) and the wild-type mice (alpha 7nAChR(+/+)). Three percent dextran sulfate sodium (DSS) was used for the creation of IBD mice model and lipopolysaccharides (LPS)/DSS as an inflammatory stressor in murine bone marrow-derived macrophages (BMDMs). The severity of IBD was determined and HE staining as well as enzyme-linked immunosorbent assay (ELISA) and real-time PCR were used to detect the level of inflammatory activation. Western blot was used to determine the levels of autophagy-related proteins. Transmission electron microscopy and mRFP-GFP-LC3 plasmid were applied to determine the levels of autophagy. We demonstrated that deficiency in alpha 7nAChR produced a detrimental effect on IBD severity and inflammatory reaction in DSS-induced colitis models. Those effects were led to via autophagy dysfunction. alpha 7nAChR deficiency attenuated the protective and anti-inflammatory effect of autophagy inducer in IBD mice and BMDMs challenged with LPS/DSS. The alleviative effect of activating alpha 7nAChR was attenuated through inhibiting adenosine 5 '-monophosphate (AMP)-activated protein kinase (AMPK)-mediated signaling. In conclusion, alpha 7nAChR contributes to alleviate IBD through the induction of AMPK-mammalian target of rapamycin rabbit (mTOR)-p70 ribosomal protein S6 kinase (p70S6K)-mediated autophagy, thus providing a novel target for the treatment of IBD.