Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis
By J. Huston, M. Ochani, M. Rosas‐Ballina, H. Liao, K. Ochani, Valentin A. Pavlov, M. Gallowitsch‐Puerta, M. Ashok, C. Czura, B. Foxwell and 2 more. Journal of Experimental Medicine, 2006
666 citations recorded by the source corpus.
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 α7 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 α7 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 α7 agonists to inhibit proinflammatory cytokine production during infection and tissue injury.
Subfields: Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine, Neurology
View Paper: https://www.semanticscholar.org/paper/becb0b83fbb622dc1d5c3b6d614fbb898c6a7e3e
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Citations in the corpus
- The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation (2007, background): “According to the recent implication of the spleen in the anti-inflammatory potential of the vagus nerve (Huston et al., 2006), future studies are needed to determine whether the inhibition of the leukocyte migration in the carrageenan air pouch mode is due to the effect of vagus nerve on the foot or”
- Physiology and immunology of the cholinergic antiinflammatory pathway. (2007, positive): “Vagus nerve stimulation in WT mice inhibits TNF synthesis in spleen, liver, and blood but not in α 7 nAChR subunit–knockout animals (28).”
- Harmful molecular mechanisms in sepsis (2008, result): “Recent studies have shown that the branch of the vagus nerve that innervates the spleen is crucial for the suppression of cytokine synthesis in sepsi”
- Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia (2008, methodology): “Vagus nerve stimulation was performed as described previously (12).”
- Reflex control of immunity (2009, background): “Direct electrical stimulation of the cholinergic anti-inflammatory pathway with electrodes that generate action potentials in the vagus nerve significantly inhibits cytokine production by innate immune cells in the spleen, liver, gastrointestinal tract, heart and other tissues that are innervated by”