Cholinergic anti-inflammatory pathway

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The cholinergic anti-inflammatory pathway regulates the innate immune response to injury, pathogens, and tissue ischemia. It is the efferent, or motor arm of the inflammatory reflex, the neural circuit that responds to and regulates the inflammatory response.[1]

Regulating the immune response[edit]

In 1987 a study showed that administration of armin, an irreversible inhibitor of acetylcholinesterase, by injection 24 hours before sepsis modelling invoked essential depression of a lethality of mice from experimental infectious process.[2] Later (in 1995) this data has been confirmed at cholinergic stimulation by other cholinomimetics.[2][3] Inhibitors of acetylcholinesterase can cause higher accessibility of acetylcholine and activation of cholinergic anti-inflammatory pathway as well.

Tumor necrosis factors (TNF) (and other cytokines) are produced by cells of the innate immune system during local injury and infection. These contribute to initiating a cascade of mediator release, and recruiting inflammatory cells to the site of infection to contain infection, referred to as "innate immunity.". TNF amplifies and prolongs the inflammatory response by activating other cells to release interleukin-1 (IL-1), high mobility group B1 (HMGB1) and other cytokines.[4] These inflammatory cytokine responses confer protective advantages to the host at the site of bacterial infection. A “beneficial” inflammatory response is limited, resolves in 48–72 hours, and does not spread systemically. The cholinergic anti-inflammatory pathway provides a braking effect on the innate immune response which protects the body against the damage that can occur if a localized inflammatory response spreads beyond the local tissues, which results in toxicity or damage to the kidney, liver, lungs, and other organs.[5]

Neurophysiological and immunological mechanism[edit]

The vagus nerve is the tenth cranial nerve. It regulates heart rate, broncho-constriction, digestion, and the innate immune response. The vagus nerve innervates the celiac ganglion, the site of origin of the splenic nerve. Stimulation of the efferent vagus nerve slows heart rate, induces gastrointestinal motility, and inhibits TNF production in spleen.[1] Stimulation of the efferent pathway of the vagus nerve releases acetylcholine, the neurotransmitter which interacts with the α7 subunit of the nicotinic AChR (α7 nAChR). nAChR is expressed on the cell membrane of macrophages and other cytokine secreting cells. Binding of acetylcholine to nAChR activates intracellular signal transduction which inhibits the release of pro-inflammatory cytokines. Ligand receptor signaling does suppress production of anti-inflammatory cytokines (IL-10).[6]

See also[edit]


  1. ^ a b Rosas-Ballina M, Ochani M, Parrish WR, Ochani K, Harris YT, Huston JM, Chavan S, Tracey KJ (August 2008). "Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia". Proc. Natl. Acad. Sci. U.S.A. 105 (31): 11008–13. doi:10.1073/pnas.0803237105. PMC 2504833. PMID 18669662.
  2. ^ a b Zabrodskiĭ, PF (1987). "Effect of armin on nonspecific resistance factors of the body and on the primary humoral immune response". Farmakologiia i toksikologiia. 50 (1): 57–60. PMID 3549354.
  3. ^ Zabrodskiĭ PF (August 1995). "[Change in the non-specific anti-infection resistance of the body exposed to cholinergic stimulation]". Biull Eksp Biol Med (in Russian). 120 (8): 164–6. PMID 7579275.
  4. ^ Czura CJ, Wang H, Tracey KJ (2001). "Dual roles for HMGB1: DNA binding and cytokine". J. Endotoxin Res. 7 (4): 315–21. doi:10.1177/09680519010070041401. PMID 11717586.
  5. ^ Tracey KJ (June 2009). "Reflex control of immunity". Nat. Rev. Immunol. 9 (6): 418–28. doi:10.1038/nri2566. PMC 4535331. PMID 19461672.
  6. ^ Chatterjee PK, Al-Abed Y, Sherry B, Metz CN (November 2009). "Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation". Am. J. Physiol., Cell Physiol. 297 (5): C1294–306. doi:10.1152/ajpcell.00160.2009. PMC 2777398. PMID 19741199.