Vagus nerve stimulation promotes resolution of inflammation by a mechanism that involves Alox15 and requires the α7nAChR subunit

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 22; p. e2023285119
• Main Authors: Caravaca, April S, Gallina, Alessandro L, Tarnawski, Laura, Shavva, Vladimir S, Colas, Romain A, Dalli, Jesmond, Malin, Stephen G, Hult, Henrik, Arnardottir, Hildur, Olofsson, Peder S
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 31.05.2022
• Subjects: a7nAChR gene; Alox15 gene; Alox15 protein; alpha7 Nicotinic Acetylcholine Receptor; alpha7 Nicotinic Acetylcholine Receptor - genetics; animal; animal cell; animal experiment; animal model; animal tissue; Animals; Arachidonate 12-Lipoxygenase; Arachidonate 12-Lipoxygenase - genetics; Arachidonate 12-Lipoxygenase - metabolism; Arachidonate 15-Lipoxygenase; Arachidonate 15-Lipoxygenase - genetics; Arachidonate 15-Lipoxygenase - metabolism; autacoid; autonomic reflex; Biological Sciences; Biosynthesis; bungarotoxin receptor; cervonic acid; Cholinergics; controlled study; disease duration; Disease Models, Animal; docosapentaenoic acid; efferocytosis; ex vivo study; Exudates; Exudation; gene; genetics; In vivo methods and tests; in vivo study; Inflammation; Inflammation - therapy; Inflammation Mediators; Inflammation Mediators - metabolism; Inflammatory diseases; Leukocytes (neutrophilic); lipid mediators; lipidomics; Lipids; male; Medicin och hälsovetenskap; Mice; Mice, Mutant Strains; mouse; Nerves; nervous system inflammation; neuroinflammation; nonhuman; Peritoneum; peritoneum exudate; Peritonitis; physiology; Reflexes; Stimulation; surgical technique; Vagus Nerve; Vagus Nerve - physiology; Vagus Nerve Stimulation; zymosan; autonomic reflex; lipid mediators; vagus nerve; neuroinflammation; peritonitis
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2023285119

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.