Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis.
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.
Huston
Jared M
JM
Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, NY 11030, USA.
Ochani
Mahendar
M
Rosas-Ballina
Mauricio
M
Liao
Hong
H
Ochani
Kanta
K
Pavlov
Valentin A
VA
Gallowitsch-Puerta
Margot
M
Ashok
Mala
M
Czura
Christopher J
CJ
Foxwell
Brian
B
Tracey
Kevin J
KJ
Ulloa
Luis
L
D000109:Acetylcholine / Q000037:antagonists & inhibitors* / Q000502:physiology*; D000818:Animals; D019446:Endotoxemia / Q000188:drug therapy / Q000276:immunology* / Q000401:mortality; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D011917:Rats, Inbred Lew; D018805:Sepsis / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013156:Splenectomy
D000109:Acetylcholine