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.[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]

## Relationship with psychological stress[edit]

Inflammatory markers tend to be elevated in people who experience various forms of psychological stress.[7][8] Psychological stress increases activation in the sympathetic branch of the autonomic nervous system (ANS) resulting in increased adrenergic input to the spleen via sympathetic nerve fibers descending into lymphoid tissues.[9][10] The main neural structure responsible for down-regulating psychological stress levels is the prefrontal cortex (PFC). The PFC counters sympathetic nervous system activation by inhibiting arousal-eliciting activity in pre-autonomic neural structures such as the amygdala[11] and hypothalamus[12] and by increasing activity in the vagal branch of the ANS.[13] Thus, the prefrontal input to the ANS modulate the inflammatory response to psychological stress in part via the cholinergic anti-inflammatory pathway.[14] In recent years, this PFC-Vagus Nerve-Spleen axis has been linked to cellular senescence[15][16] and various pathologies such as neurodegenerative diseases and cancer.[17][18]

## See also[edit]

### Branches of medicine[edit]

* Behavioral neuroscience
* Biological psychiatry
* Epidemiology
* Immunology
* Molecular biology
* Neuroanatomy
* Neurobiology
* Neurochemistry
* Neurophysics
* Neurology
* Neuropharmacology
* Psychiatry
* Psychoneuroendocrinology
* Psychoneuroimmunology

### Related topics[edit]

* Allostatic load
* Cancer
* Cellular senescence
* Fight-or-flight response
* Healing environments
* Heart rate variability
* Immuno-psychiatry
* Infectious diseases
* Inflammatory reflex
* Neural top down control of physiology
* Neurodegenerative diseases
* PANDAS
* Post-traumatic stress disorder
* Psychosomatic medicine
* Sepsis
* Somatic marker hypothesis
* Stress management

### Neuroanatomy[edit]

* Amygdala
* Hypothalamus
* Prefrontal cortex
* Solitary nucleus
* Splenic plexus
* Vagus nerve

### Neurotransmitter Pathways[edit]

* List of regions in the human brain § Neurotransmitter pathways

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## References[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. Bibcode:2008PNAS..10511008R. doi:10.1073/pnas.0803237105. PMC 2504833. PMID 18669662.
2. ^ 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). "Variation in antiinfectious nonspecific resistance of the organism caused by cholinergic stimulation". Bulletin of Experimental Biology and Medicine. 120 (2): 809–811. doi:10.1007/BF02445960. S2CID 31513646.
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.
7. ^ Maydych V (April 2019). "The Interplay Between Stress, Inflammation, and Emotional Attention: Relevance for Depression". Frontiers in Neuroscience. 13: 384. doi:10.3389/fnins.2019.00384. PMC 6491771. PMID 31068783.
8. ^ Segerstrom SC, Miller GE (July 2004). "Psychological Stress and the Human Immune System: A Meta-Analytic Study of 30 Years of Inquiry". Psychol. Bull. 130 (4): 601–630. doi:10.1037/0033-2909.130.4.601. PMC 1361287. PMID 15250815.
9. ^ Madden KS, Sanders VM, Felten DL (1995). "Catecholamine influences and sympathetic neural modulation of immune responsiveness". Annu Rev Pharmacol Toxicol. 35: 417–448. doi:10.1146/annurev.pa.35.040195.002221. PMID 7598501.
10. ^ Vizi ES (June 1995). "Receptor-mediated local fine-tuning by noradrenergic innervation of neuroendocrine and immune systems". Ann N Y Acad Sci. 851: 388–396. doi:10.1111/j.1749-6632.1998.tb09012.x. PMID 9668629. S2CID 43091190.
11. ^ Golkar A, Landsdorf TB, Olsson A, et al. (November 2012). "Distinct contributions of the dorsolateral prefrontal and orbitofrontal cortex during emotion regulation". PLOS ONE. 7 (11): e48107. Bibcode:2012PLoSO...748107G. doi:10.1371/journal.pone.0048107. PMC 3492343. PMID 23144849.
12. ^ Seeley WW, Menon V, Schatzberg AF, et al. (February 2007). "Dissociable intrinsic connectivity networks for salience processing and executive control". J. Neurosci. 27 (9): 2349–2356. doi:10.1523/JNEUROSCI.5587-06.2007. PMC 2680293. PMID 17329432.
13. ^ Thayer JF, Ahs F, Fredrikson M, et al. (December 2012). "A meta-analysis of heart rate variability and neuroimaging studies: implications for heart rate variability as a marker of stress and health". Neurosci Biobehav Rev. 36 (2): 747–756. doi:10.1016/j.neubiorev.2011.11.009. PMID 22178086. S2CID 2512272.
14. ^ Williams DP, Koenig J, Carnevali L, et al. (August 2019). "Heart rate variability and inflammation: A meta-analysis of human studies". Brain Behav. Immun. 80: 219–226. doi:10.1016/j.bbi.2019.03.009. PMID 30872091. S2CID 78091147.
15. ^ Ask TF, Lugo RG, Sütterlin S (October 2018). "The Neuro-Immuno-Senescence Integrative Model (NISIM) on the Negative Association Between Parasympathetic Activity and Cellular Senescence". Front. Neurosci. 12: 726. doi:10.3389/fnins.2018.00726. PMC 6194361. PMID 30369866.
16. ^ Epel E, Daubenmier J, Moskowitz JT, et al. (August 2009). "Can meditation slow rate of cellular aging? Cognitive stress, mindfulness, and telomeres". Ann N Y Acad Sci. 1172 (1): 34–53. Bibcode:2009NYASA1172...34E. doi:10.1111/j.1749-6632.2009.04414.x. PMC 3057175. PMID 19735238.
17. ^ De Couck M, Mravec B, Gidron Y (April 2012). "You may need the vagus nerve to understand pathophysiology and to treat diseases". Clinical Science. 122 (7): 323–328. doi:10.1042/CS20110299. PMC 2777398. PMID 19741199.
18. ^ De Couck M, Caers R, Spiegel D, Gidron Y (July 2018). "The Role of the Vagus Nerve in Cancer Prognosis: A Systematic and a Comprehensive Review". J. Oncol. 2018: 1236787. doi:10.1155/2018/1236787. PMC 6051067. PMID 30057605.