The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis.
BACKGROUND
The nervous system, through the vagus nerve, can down-regulate inflammation in vivo by decreasing the release of tumor necrosis factor- alpha 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.


CONCLUSIONS
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.
van Westerloo
David J
DJ
Laboratory of Experimental Internal Medicine and Department of Gastroenterology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. d.j.vanwesterloo@amc.uva.nl
Giebelen
Ilona A J
IA
Florquin
Sandrine
S
Daalhuisen
Joost
J
Bruno
Marco J
MJ
de Vos
Alex F
AF
Tracey
Kevin J
KJ
van der Poll
Tom
T
D000818:Animals; D016207:Cytokines / Q000502:physiology; D004927:Escherichia coli Infections / Q000276:immunology; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D015213:Neuroimmunomodulation; D009538:Nicotine / Q000494:pharmacology; D010538:Peritonitis / Q000276:immunology*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology; D018805:Sepsis / Q000276:immunology*; D014628:Vagotomy; D014630:Vagus Nerve / Q000502:physiology
D016207:Cytokines; D011978:Receptors, Nicotinic; D009538:Nicotine