title: Enteric glia cells are critical to limiting the intestinal inflammatory response after injury.
abstract: Vagal nerve stimulation (VNS) has been shown to limit intestinal inflammation following injury; however, a direct connection between vagal terminals and resident intestinal immune cells has yet to be identified. We have previously shown that enteric glia cell (EGC) expression is increased after injury through a vagal-mediated pathway to help restore gut barrier function. We hypothesize that EGCs modulate immune cell recruitment following injury and relay vagal anti-inflammatory signals to resident immune cells in the gut. EGCs were selectively ablated from an isolated segment of distal bowel with topical application of benzalkonium chloride (BAC) in male mice. Three days following BAC application, mice were subjected to an ischemia-reperfusion injury (I/R) by superior mesenteric artery occlusion for 30 min. VNS was performed in a separate cohort of animals. EGC+and EGC-segments were compared utilizing histology, flow cytometry, immunohistochemistry, and intestinal permeability. VNS significantly reduced immune cell recruitment after I/R injury in EGC+segments with cell percentages similar to sham. VNS failed to limit immune cell recruitment in EGC-segments. Histologic evidence of gut injury was diminished with VNS application in EGC+segments, whereas EGC-segments showed features of more severe injury. Intestinal permeability increased following I/R injury in both EGC+and EGC-segments. Permeability was significantly lower after VNS application compared with injury alone in EGC+segments only (95.1 ± 30.0 vs. 217.6 ± 21.7 μg/ml,P< 0.05). Therefore, EGC ablation uncouples the protective effects of VNS, suggesting that vagal-mediated signals are translated to effector cells through EGCs.NEW & NOTEWORTHYIntestinal inflammation is initiated by local immune cell activation and epithelial barrier breakdown, resulting in the production of proinflammatory mediators with subsequent leukocyte recruitment. Vagal nerve stimulation (VNS) has been shown to limit intestinal inflammation following injury; however, direct connection between vagal terminals and resident intestinal immune cells has yet to be identified. Here, we demonstrate that intact enteric glia cells are required to transmit the gut anti-inflammatory effects of VNS.
authors.affiliation: Division of Trauma, Surgical Critical Care, Burns, and Acute Care Surgery, Department of Surgery, University of California, San Diego Health Sciences, San Diego, California.
authors.forename: Simone
authors.initials: S
authors.lastname: Langness
authors.affiliation: Division of Trauma, Surgical Critical Care, Burns, and Acute Care Surgery, Department of Surgery, University of California, San Diego Health Sciences, San Diego, California.
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Kojima
authors.affiliation: Division of Trauma, Surgical Critical Care, Burns, and Acute Care Surgery, Department of Surgery, University of California, San Diego Health Sciences, San Diego, California.
authors.forename: Raul
authors.initials: R
authors.lastname: Coimbra
authors.affiliation: Division of Trauma, Surgical Critical Care, Burns, and Acute Care Surgery, Department of Surgery, University of California, San Diego Health Sciences, San Diego, California.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Eliceiri
authors.affiliation: Division of Trauma, Surgical Critical Care, Burns, and Acute Care Surgery, Department of Surgery, University of California, San Diego Health Sciences, San Diego, California tcostantini@ucsd.edu.
authors.forename: Todd W
authors.identifier: http://orcid.org/0000-0002-0215-5327
authors.initials: TW
authors.lastname: Costantini
mesh_terms: D000818:Animals; D007249:Inflammation / Q000378:metabolism* / Q000628:therapy; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000098:blood supply*; D008297:Male; D051379:Mice; D009457:Neuroglia / Q000378:metabolism*; D010539:Permeability; D015427:Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D055536:Vagus Nerve Stimulation
keywords: enteric glia cells; entric neurons; ischemia-reperfusion; vagal anti-inflammatory