期刊
INFLAMMATION
卷 42, 期 5, 页码 1666-1679出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10753-019-01027-9
关键词
alpha7 nicotinic acetylcholine receptor; inflammatory bowel disease; autophagy; lipopolysaccharides; dextran sulfate sodium
资金
- General Hospital of the Chinese People's Liberation Army [2018ZD-006]
- National Key R&D Program of China [2017YFC1308800, 2018YFC1313103]
- National Natural Science Foundation of China [81670473, 81873546]
- Three Engineering Training Funds in Shenzhen [SYLY201718]
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.
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