The Cholinergic Anti‐Inflammatory Pathway Regulates the Host Response during Septic Peritonitis

Westerloo, David J. van; Giebelen, Ilona A. J.; Florquin, Sandrine; Daalhuisen, Joost; Bruno, Marco J.; Vos, Alex F. de; Tracey, Kevin J.; Poll, Tom van der

doi:10.1086/430323

Cited by 285 publications

(249 citation statements)

References 31 publications

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“…In contrast, our study suggested that unilateral vagotomy not only aggravated the abnormality of ICM rats and increased the inducibility quotient of ventricular arrhythmias but also attenuated the effects of eliciting CAP. It was also reported that vagotomy attenuated the anti‐inflammatory effect of CAP and thereby enhanced cytokine release in response to LPS treatment 41, 42. Thus, vagotomy, performed in an ICM rat, increased the release of cytokines and collagens and altered the sympathetic/parasympathetic ratio, which served as a harmful role of ventricular arrhythmia.…”

Section: Discussionmentioning

confidence: 94%

Alteration of Cholinergic Anti‐Inflammatory Pathway in Rat With Ischemic Cardiomyopathy–Modified Electrophysiological Function of Heart

Shi

et al. 2017

JAHA

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BackgroundWith chronic ischemia after myocardial infarction, the resulting scar tissue result in electrical and structural remodeling vulnerable to an arrhythmogenic substrate. The cholinergic anti‐inflammatory pathway elicited by vagal nerve via α7 nicotinic acetylcholine receptors (α7‐nAChR) can modulate local and systemic inflammatory responses. Here, we aimed to clarify a novel mechanism for the antiarrhythmogenic properties of vagal nerve during the ischemic cardiomyopathy (ICM).Methods and ResultsLeft anterior descending artery of adult male Sprague‐Dawley rats was ligated for 4 weeks to develop ICM. Western blot revealed that eliciting the cholinergic anti‐inflammatory pathway by nicotine treatment showed a significant reduction in the amounts of collagens, cytokines, and other inflammatory mediators in the left ventricular infarcted border zone via inhibited NF‐κB activation, whereas it increased the phosphorylated connexin 43. Vagotomy inhibited the anti‐inflammatory, anti‐fibrosis, and anti‐arrhythmogenic effect of nicotine administration. And immunohistochemistry confirmed that the nicotine administration‐induced increase of connexin 43 was located in intercellular junctions. Furthermore nicotine treatment suppressed NF‐κB activation in lipopolysaccharide‐stimulated RAW264.7 cells, and α‐bungarotoxin (an α7‐nAChR selective antagonist) partly inhibited the nicotine‐treatment effect. In addition, 4‐week nicotine administration slightly improved the cardiac function, increased cardiac parasympathetic tone, decreased the prolonged QTc, and decreased the arrhythmia score of programmed electric stimulation‐induced ventricular arrhythmia.ConclusionsEliciting the cholinergic anti‐inflammatory pathway exerts anti‐arrhythmogenic effects against ICM‐induced ventricular arrhythmia accompanied by downregulation of cytokines, downgenerating of collagens, decrease in sympathetic/parasympathetic ratio, and prevention of the loss of phosphorylated connexin 43 during ICM. Our findings may suggest a promising therapy for the generation of ICM‐induced ventricular arrhythmia by eliciting the cholinergic anti‐inflammatory pathway.

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Section: Discussionmentioning

confidence: 94%

Alteration of Cholinergic Anti‐Inflammatory Pathway in Rat With Ischemic Cardiomyopathy–Modified Electrophysiological Function of Heart

Shi

et al. 2017

JAHA

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“…Peritonitis was induced by i.p. injection of 10 4 CFU E. coli O18:K1, as described previously (14,15). In one experiment, 200 g of LPS (E. coli 0111:B4; SigmaAldrich) was injected i.p.…”

Section: Animals and Designmentioning

confidence: 99%

Matrix Metalloproteinase-9 Deficiency Impairs Host Defense against Abdominal Sepsis

Renckens¹,

Roelofs²,

Florquin³

et al. 2006

The Journal of Immunology

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109

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Matrix metalloproteinase (MMP)-9 is involved in extracellular matrix degradation and leukocyte migration. To determine the role of MMP-9 in the innate immune response to peritonitis, MMP-9 gene-deficient (MMP-9−/−) and normal wild-type mice were i.p. infected with Escherichia coli. MMP-9 mRNA and pro-MMP-9 protein levels increased rapidly upon induction of peritonitis. Although MMP-9−/− neutrophils showed a normal phagocytosis of E. coli in vitro, MMP-9−/− mice displayed a reduced resistance against E. coli peritonitis, as indicated by an enhanced bacterial outgrowth in the peritoneal cavity and increased dissemination of the infection. Furthermore, the cytokine response to LPS was not influenced by MMP-9 deficiency. However, during E. coli peritonitis, MMP-9−/− mice showed much higher peritoneal chemokine and cytokine levels compared with wild-type mice. Despite the increased local chemokine concentrations, MMP-9−/− mice displayed a diminished recruitment of leukocytes to the site of infection, indicating that cellular migration was impaired. Moreover, MMP-9−/− mice developed more severe distant organ damage during infection. These data suggest that MMP-9 is an essential component of an effective host response to E. coli peritonitis.

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“…This pathway is controlled by brain muscarinic networks that depend on an intact vagus nerve to attenuate systemic cytokine production (5). Activation of the cholinergic antiinflammatory pathway, either by electrical stimulation of the vagus nerve or through pharmacological approaches, has been shown to significantly ameliorate cytokine-mediated disease models, including endotoxemia (2,6), sepsis (6,7), colitis (8), pancreatitis (9), and ischemia reperfusion (10,11).…”

mentioning

confidence: 99%

Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia

Rosas-Ballina¹,

Ochani²,

Parrish³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

619

569

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The autonomic nervous system maintains homeostasis through its sympathetic and parasympathetic divisions. During infection, cells of the immune system release cytokines and other mediators that cause fever, hypotension, and tissue injury. Although the effect of cytokines on the nervous system has been known for decades, only recently has it become evident that the autonomic nervous system, in turn, regulates cytokine production through neural pathways. We have previously shown that efferent vagus nerve signals regulate cytokine production through the nicotinic acetylcholine receptor subunit ␣7, a mechanism termed ''the cholinergic antiinflammatory pathway.'' Here, we show that vagus nerve stimulation during endotoxemia specifically attenuates TNF production by spleen macrophages in the red pulp and the marginal zone. Administration of nicotine, a pharmacological agonist of ␣7, attenuated TNF immunoreactivity in these specific macrophage subpopulations. Synaptophysin-positive nerve endings were observed in close apposition to red pulp macrophages, but they do not express choline acetyltransferase or vesicular acetylcholine transporter. Surgical ablation of the splenic nerve and catecholamine depletion by reserpine indicate that these nerves are catecholaminergic and are required for functional inhibition of TNF production by vagus nerve stimulation. Thus, the cholinergic antiinflammatory pathway regulates TNF production in discrete macrophage populations via two serially connected neurons: one preganglionic, originating in the dorsal motor nucleus of the vagus nerve, and the second postganglionic, originating in the celiacsuperior mesenteric plexus, and projecting in the splenic nerve.brain ͉ cytokine ͉ innate ͉ spleen ͉ vagus T he autonomic nervous system is divided into two major branches based on anatomy and function. These divisions, sympathetic and parasympathetic, control organ function through a set of two serially connected neurons, the first of which is located in the CNS and the second in the peripheral ganglia. Typically, parasympathetic neurons originate in the brainstem medulla and sacral portion of the spinal cord, and the ganglia are located close to or within the innervated organ. Sympathetic neurons originate in the thoracic and lumbar portion of the spinal cord, and the ganglia are situated close to the spinal cord.

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The Cholinergic Anti‐Inflammatory Pathway Regulates the Host Response during Septic Peritonitis

Abstract: These data provide the first evidence, to our knowledge, of an important role of the vagus nerve in regulating the innate immune response to a severe bacterial infection.

Cited by 285 publications

References 31 publications

Alteration of Cholinergic Anti‐Inflammatory Pathway in Rat With Ischemic Cardiomyopathy–Modified Electrophysiological Function of Heart

Alteration of Cholinergic Anti‐Inflammatory Pathway in Rat With Ischemic Cardiomyopathy–Modified Electrophysiological Function of Heart

Matrix Metalloproteinase-9 Deficiency Impairs Host Defense against Abdominal Sepsis

Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia

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