Electroacupuncture ameliorates intestinal inflammation by activating α7nAChR-mediated JAK2/STAT3 signaling pathway in postoperative ileus.
Electroacupuncture ameliorates intestinal inflammation by activating α7nAChR-mediated JAK2/STAT3 signaling pathway in postoperative ileus.
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作者：
Yang NN;Yang JW;Ye Y;Huang J;Wang L;Wang Y;Su XT;Lin Y;Yu FT;Ma SM;Qi LY;Lin LL;Wang LQ;Shi GX;Li HP;Liu CZ
肌层巨噬细胞产生的炎性细胞因子在很大程度上促成了术后肠梗阻（POI）的病理征象。电针主要或部分通过激活迷走神经传出神经来抑制炎症。本研究的目的是探讨EA刺激后肢区域改善POI炎症的机制。方法：在肠操作（IM）诱导POI后24 h，观察小鼠肠道蠕动和炎症反应。采用流式细胞术、Western Blot、qPCR和免疫荧光法检测大鼠肠道肌层局部免疫应答、巨噬细胞、α7烟碱乙酰胆碱受体（α7nAChR）、Janus激酶2 （JAK2）和转录信号转导激活因子3 （STAT3）的表达。α7nAChR拮抗剂（甲基莱卡乌碱和α-邦加罗毒素）和JAK2/STAT3抑制剂（AG490和WP1066）也在EA前给予小鼠亚组。在副交感神经通路中，颈部迷走神经切断和膈下迷走神经切断后测定肠道运动和炎症。采用免疫荧光法检测迷走神经背运动核（DMV）胆碱能神经元γ -吸收测定氨基丁酸（GABAA）受体的表达，并观察双库库碱（GABAA受体拮抗剂）或肌西莫（GABAA受体激动剂）对DMV微注射的反应。结果：EA能抑制肠道炎症，促进胃肠蠕动。在机制上，EA激活了巨噬细胞中α 7nachr介导的JAK2/STAT3信号通路，减少了炎症细胞因子的产生。此外，我们还证明了后肢区刺激通过抑制DMV中GABAA受体的表达来促进迷走神经传出输出，从而改善炎症。结论：后肢EA抑制DMV神经元GABAA受体的表达，DMV神经元兴奋的迷走神经通过激活α 7nachr介导的JAK2/STAT3信号通路抑制im诱导的炎症反应。
Inflammatory cytokines produced by muscularis macrophages largely contribute to the pathological signs of postoperative ileus (POI). Electroacupuncture (EA) can suppress inflammation, mainly or partly via activation of vagal efferent. The goal of this study was to investigate the mechanisms by which EA stimulation at an hindlimb region ameliorates inflammation in POI. Methods: Intestinal motility and inflammation were examined after 24 h after intestinal manipulation (IM)-induced POI in mice. Local immune response in the intestinal muscularis, expression of macrophages, α7 nicotinic acetylcholine receptor (α7nAChR), Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) were determined by flow cytometry, Western Blot, qPCR and immunofluorescence. The effects of α7nAChR antagonists (methyllycaconitine and α-bungarotoxin) and JAK2/STAT3 inhibitors (AG490 and WP1066) were also administered in a subset of mice prior to EA. In the parasympathetic pathways, intestinal motility and inflammation were determined after cervical vagotomy and sub-diaphragmatic vagotomy. The expression of gamma absorptiometry aminobutyric acid (GABAA) receptor in dorsal motor nucleus of vagal (DMV) cholinergic neurons was assessed by immunofluorescence and the response to DMV microinjection of bicuculine (antagonist of GABAA receptor) or muscimol (agonist of GABAA receptor) were assessed. Results: EA suppressed intestinal inflammation and promoted gastrointestinal motility. Mechanistically, EA activated the α7nAChR-mediated JAK2/STAT3 signaling pathway in macrophages which reduced the production of inflammatory cytokines. Furthermore, we also demonstrated that hindlimb region stimulation drove vagal efferent output by inhibiting the expression of GABAA receptor in DMV to ameliorate inflammation. Conclusions: The present study revealed that EA of hindlimb regions inhibited the expression of GABAA receptor in DMV neurons, whose excited vagal nerve, in turn suppressed IM-induced inflammation via activation of α7nAChR-mediated JAK2/STAT3 signaling pathway.
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