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标题：Vagus nerve stimulation promotes resolution of inflammation by a mechanism that involves Alox15 and requires the α7nAChR subunit
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作者：April S. Caravaca ; Alessandro L. Gallina ; Laura Tarnawski 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：22
DOI：10.1073/pnas.2023285119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance Resolution of inflammation is an active process that restores tissue homeostasis and prevents the development of chronic inflammatory diseases. The mechanisms that regulate resolution of inflammation are only partially understood. Here, we showed that activation of the vagus nerve accelerated resolution of inflammation. Electrical stimulation of the vagus nerve in vivo increased levels of select specialized proresolving mediators in inflammation. Experiments in genetic mouse models revealed that the mechanism involved 12/15-lipoxgenase (Alox15), a key enzyme for biosynthesis of the identified mediators, and required the α7-nicotinic acetylcholine receptor subunit. The findings indicate that electrical signals in the vagus nerve activate a cholinergic signal promoting Alox15-dependent lipid mediator biosynthesis and accelerating resolution of inflammation, providing additional insights into neural regulation of inflammation. Nonresolving inflammation underlies a range of chronic inflammatory diseases, and therapeutic acceleration of resolution of inflammation may improve outcomes. Neural reflexes regulate the intensity of inflammation (for example, through signals in the vagus nerve), but whether activation of the vagus nerve promotes the resolution of inflammation in vivo has been unknown. To investigate this, mice were subjected to electrical vagus nerve stimulation (VNS) or sham surgery at the cervical level followed by zymosan-induced peritonitis. The duration of inflammation resolution was significantly reduced and efferocytosis was significantly increased in mice treated with VNS as compared with sham. Lipid mediator (LM) metabololipidomics revealed that mice treated with VNS had higher levels of specialized proresolving mediators (SPMs), particularly from the omega-3 docosahexaenoic (DHA) and docosapentaenoic (n-3 DPA) metabolomes, in peritoneal exudates. VNS also shifted the ratio between proinflammatory and proresolving LMs toward a proresolving profile, but this effect by VNS was inverted in mice deficient in 12/15-lipoxgenase (Alox15), a key enzyme in this SPM biosynthesis. The significant VNS-mediated reduction of neutrophil numbers in peritoneal exudates was absent in mice deficient in the cholinergic α7-nicotinic acetylcholine receptor subunit (α7nAChR), an essential component of the inflammatory reflex. Thus, VNS increased local levels of SPM and accelerated resolution of inflammation in zymosan-induced peritonitis by a mechanism that involves Alox15 and requires the α7nAChR.
关键词：envagus nerveautonomic reflexperitonitisneuroinflammationlipid mediators