Electroacupuncture ameliorates intestinal inflammation by activating α7nAChR-mediated JAK2/STAT3 signaling pathway in postoperative ileus

Abstract

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 (GABA A ) receptor in dorsal motor nucleus of vagal (DMV) cholinergic neurons was assessed by immunofluorescence and the response to DMV microinjection of bicuculine (antagonist of GABA A receptor) or muscimol (agonist of GABA A 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 GABA A receptor in DMV to ameliorate inflammation. Conclusions: The present study revealed that EA of hindlimb regions inhibited the expression of GABA A receptor in DMV neurons, whose excited vagal nerve, in turn suppressed IM-induced inflammation via activation of α7nAChR-mediated JAK2/STAT3 signaling pathway.

Acupuncture for Primary Dysmenorrhea: A Potential Mechanism from an Anti-Inflammatory Perspective

“…A recent study had accordingly revealed that EA (10 Hz, 1 mA, plus width 0.4 ms) at ST36 could reduce the production of inflammatory cytokines by activating α7nAChRmediated JAK2/STAT3 signaling pathway in macrophages, thereby suppressing gastrointestinal inflammation and promoting its motility [17], which demonstrated the antiinflammatory and analgesic effects of EA through vagus nerve from the point of view of the complete nerve circuit. Another recent study showed that EA at ST36 with low intensity (0.5 mA) can activate sensory neurons expressing PROKR2+, thus driving the vagal-adrenal axis to play a systemic anti-inflammatory effect, and pointed out that the anti-inflammatory effect of acupuncture was related to the intensity of stimulation and the depth of acupuncture [89].…”

“…is alternative medicine has also demonstrated promising anti-inflammatory effects; therefore, it has been applied to treat inflammatory diseases [16][17][18], especially inflammatory pain [19][20][21][22]. Numerous studies have so far elucidated the underlying mechanism of acupuncture for various types of pain, including visceral pain [22,23], and it has been emphasized that anti-inflammatory effects can contribute to the analgesic mechanism of this alternative therapy.…”

Role of Neuroimmune Crosstalk in Mediating the Anti-inflammatory and Analgesic Effects of Acupuncture on Inflammatory Pain

“…In OA models, EA at Ex-LE4 ( Neixiyan ) and ST35 ( Dubi ) can significantly inhibit the activation of the NLRP3 inflammasome and the protein expression of matrix metalloproteinase-13, caspase-1, and IL-1β in cartilage tissue, thereby reducing mechanical hyperalgesia, improving the structure of articular cartilage, and reducing cartilage surface fibrillation ( B-Wang et al, 2020 ). Recently studies have shown that EA at ST36 excites the vagus nerve via its dorsal nucleus, activates the α7 nicotinic acetylcholine receptor (α7nAChR)-mediated Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway in macrophages, inhibits the expression of the inflammatory factors IL-6 and TNF-α, reduces the local immune responses in the gastrointestinal tract, and promotes the recovery of gastrointestinal motility in mice with postoperative intestinal paralysis ( Yang et al, 2021 ). These pieces of evidence suggest that macrophage polarization and the balance of related cytokines may be the main targets of acupuncture in its regulation of inflammatory pain.…”

The role of macrophage polarization and associated mechanisms in regulating the anti-inflammatory action of acupuncture: a literature review and perspectives

“…Recently, this group further demonstrated that EA at ST36 suppressed intestinal inflammation and promoted gastrointestinal motility. Mechanistically, EA activated the α7-nicotinic acetylcholine receptor (α7nAChR) -mediated JAK2/STAT3 signaling pathway in macrophages which reduced the production of inflammatory cytokines by acupuncture [ 55 ]. In addition, it has been also demonstrated that acupuncture at SP6 has an anti-inflammatory effect on peritonitis caused by carrageenan, resulting in decreased inflammatory cell infiltration and vascular permeability while increasing the levels of IL-10 [ 56 ].…”