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15 June 2005

Volume 191, Number 12
The Journal of Infectious Diseases 2005;191:2138–2148
© 2005 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2005/19112-0019$15.00
DOI: 10.1086/430323
MAJOR ARTICLE

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

David J. van Westerloo,1,2

Ilona A. J. Giebelen,1

Sandrine Florquin,3

Joost Daalhuisen,1

Marco J. Bruno,2

Alex F. de Vos,1

Kevin J. Tracey,5 and

Tom van der Poll1,4

1Laboratory of Experimental Internal Medicine and Departments of 2Gastroenterology, 3Pathology, and 4Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 5Laboratory of Biomedical Science, North Shore Long Island Jewish Research Institute, Manhasset, New York

Background.The nervous system, through the vagus nerve, can down‐regulate inflammation in vivo by decreasing the release of tumor necrosis factor–α by endotoxin‐stimulated macrophages. This anti‐inflammatory effect is mediated by an interaction between acetylcholine, the principal neurotransmitter of the vagus nerve, and cholinergic nicotinic acetylcholine receptors on macrophages.

Methods.We determined the role of this “cholinergic anti‐inflammatory pathway” during septic peritonitis induced in mice by intraperitoneal injection of live Escherichia coli. Septic peritonitis was preceded by inhibition of the cholinergic anti‐inflammatory pathway by unilateral cervical vagotomy, by stimulation of this pathway by pretreatment of mice with nicotine, or by a combination of both interventions.

Results.Initial cytokine release during septic peritonitis was enhanced after previous vagotomy and was decreased after nicotine pretreatment, independently of the integrity of the vagus nerve. Further study established that vagotomy before septic peritonitis resulted in an enhanced influx of neutrophils and a marked increase in proinflammatory cytokine levels and liver damage. Conversely, nicotine pretreatment strongly decreased cell influx, proinflammatory cytokine levels, and liver damage, whereas bacterial clearance and survival were impaired.

Discussion.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.

Received 5 October 2004; accepted 15 January 2005; electronically published 10 May 2005.

Reprints or correspondence: Dr. David J. van Westerloo, Academic Medical Center, Laboratory of Experimental Internal Medicine, Meibergdreef 9, C2‐321, 1105 AZ, Amsterdam, The Netherlands ().

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  • Potential conflicts of interest: K.J.T. is cofounder of Critical Therapeutics Inc., a pharmaceutical company developing potential future treatment modalities based on the cholinergic anti‐inflammatory pathway.

    Financial support: Academic Medical Center, Amsterdam, The Netherlands.

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