Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis.

Abstract

The innate immune system protects against infection and tissue injury through the specialized organs of the reticuloendothelial system, including the lungs, liver, and spleen. The central nervous system regulates innate immune responses via the vagus nerve, a mechanism termed the cholinergic antiinflammatory pathway. Vagus nerve stimulation inhibits proinflammatory cytokine production by signaling through the alpha7 nicotinic acetylcholine receptor subunit. Previously, the functional relationship between the cholinergic antiinflammatory pathway and the reticuloendothelial system was unknown. Here we show that vagus nerve stimulation fails to inhibit tumor necrosis factor (TNF) production in splenectomized animals during lethal endotoxemia. Selective lesioning of the common celiac nerve abolishes TNF suppression by vagus nerve stimulation, suggesting that the cholinergic pathway is functionally hard wired to the spleen via this branch of the vagus nerve. Administration of nicotine, an alpha7 agonist that mimics vagus nerve stimulation, increases proinflammatory cytokine production and lethality from polymicrobial sepsis in splenectomized mice, indicating that the spleen is critical to the protective response of the cholinergic pathway. These results reveal a specific, physiological connection between the nervous and innate immune systems that may be exploited through either electrical vagus nerve stimulation or administration of alpha7 agonists to inhibit proinflammatory cytokine production during infection and tissue injury.

• Authors: Jared M Huston, Mahendar Ochani, Mauricio Rosas-Ballina, Hong Liao, Kanta Ochani, Valentin A Pavlov, Margot Gallowitsch-Puerta, Mala Ashok, Christopher J Czura, Brian Foxwell, Kevin J Tracey, Luis Ulloa
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 203 Issue 7 Pg. 1623-8 (Jul 10 2006) ISSN: 0022-1007 [Print] United States
• PMID: 16785311 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Acetylcholine

Topics

• Acetylcholine (antagonists & inhibitors, physiology)
• Animals
• Endotoxemia (drug therapy, immunology, mortality)
• Female
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Rats
• Rats, Inbred Lew
• Sepsis (drug therapy, immunology, microbiology)
• Signal Transduction (drug effects, physiology)
• Splenectomy