Understanding the Brain

Cholinergic anti-inflammatory pathway

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The Cholinergic Anti-inflammatory Pathway regulates the innate immune response (Innate immunity) 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

For the first time (in 1987) in experiment it has been shown that armin (nonreversible inhibitor of acetylcholinesterase) at their injection 24 h prior to sepsis modelling invoke 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]

Tumor Necrosis Factor (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

The Vagus Nerve is the tenth cranial nerve. It regulates heart rate, bronchoconstriction, 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 gastric motility, and inhibits TNF production in spleen. 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 release of pro-inflammatory cytokines. Ligand receptor signaling does suppress production of anti-inflammatory cytokines (IL-10).[6]


  1. Rosas-Ballina, M.; Ochani, M.; Parrish, W. R.; Ochani, K.; Harris, Y. T.; Huston, J. M.; Chavan, S.; Tracey, K. J. (2008). "Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia". Proceedings of the National Academy of Sciences 105 (31): 11008–13. doi:10.1073/pnas.0803237105. PMC 2504833. PMID 18669662. 
  2. 2.0 2.1 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 (1995). "Change in the non-specific anti-infection resistance of the body exposed to cholinergic stimulation". Biulleten' eksperimental'noi biologii i meditsiny 120 (8): 164–6. PMID 7579275. 
  4. Czura, Christopher J.; Haichao Wang, Haichao; Tracey, Kevin J. (2001). "Dual roles for HMGB1: DNA binding and cytokine". Journal of Endotoxin Research 7 (4): 315–21. doi:10.1177/09680519010070041401. PMID 11717586. 
  5. Tracey, Kevin J. (2009). "Reflex control of immunity". Nature Reviews Immunology 9 (6): 418–28. doi:10.1038/nri2566. PMID 19461672. 
  6. Chatterjee, P. K.; Al-Abed, Y.; Sherry, B.; Metz, C. N. (2009). "Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation". AJP: Cell Physiology 297 (5): C1294–306. doi:10.1152/ajpcell.00160.2009. PMC 2777398. PMID 19741199. http://ajpcell.physiology.org/cgi/pmidlookup?view=long&pmid=19741199.