Cholinergic anti-inflammatory pathway

The Cholinergic Anti-inflammatory Pathway governs the inflammatory response to pathogens, ischemia, injury, and pro-inflammatory cytokines in a highly regulated and reflexive manner. This pathway controls the finely tuned cytokine balance and allows for post-inflammation tissue recovery.

The Regulated Immune Response to Bacterial Infection
Lipopolysaccharide from the bacterial cell wall is a potent stimulus for Tumor Necrosis Factor-alpha (TNF-α) synthesis. TNF-α acts as a key mediator in the local inflammatory immune response by initiating a cascade of cytokine release, recruiting macrophages to the site of infection, and cause blood clotting to contain the infection. TNF-α amplifies and prolongs the inflammatory response by activating other cells to release interleukin-1 (IL-1), as well as release high mobility group B1 (HMGB1) from necrosed tissue cells. This response will result in the site of bacterial infection being chemically destroyed by nitric oxide (NO) and reactive oxygen species and phagocytized by macrophage. In a “successful” inflammatory response, the duration and magnitude of TNF-α release is limited and it is not released systemically. After the pathogen is destroyed; the anti-inflammatory cytokines (namely IL-10), glucocorticoids, and TNF-α will repair the damaged tissue.

Sepsis
Originally, sepsis was believed to result from invading bacteria itself, but later found that the host’s system proteins, like TNF-α and HMGB1, induced sepsis as a response. Sepsis is caused either when cytokine production increases to an extent that it escapes the local infection or when infection enters the blood stream. Victims of septic shock experience fever, falling blood pressure, myocardial suppression, headache, dehydration, renal failure, and respiratory arrest. Body organs fail and death may result from lethal septic shock

Cholinergic Anti-inflammatory pathway
The Vagus Nerve is often considered as being the single most important nerve in the body. It is known for its cholinergic effect on heart rate, bronchoconstriction, and digestion. Stimulation of the efferent vagus nerve slows heart rate, induces gastric motility, dilation of arterioles, and constriction of pupils. Besides the heart, the vagus nerve also extends to the gastro-intestinal tract, spleen, and liver. These are known areas that supply majority of damaging cytokines. Innervation of the efferent pathway of the vagus nerve releases acetylcholine onto the α7 subunit of the nicotinic AChR (α7 nAChR) onto LPS activated macrophages, limiting the release of pro-inflammatory cytokines. This does not affect the production of anti-inflammatory cytokines (IL-10).



Benefits of Cholinergic Anti-inflammatory
The diffusible anti-inflammatory network is slow, distributed, non-integrated, and dependent on concentration gradients to work. In contrast, the cholinergic anti-inflammatory pathway is discrete, fast, short-lived, and localized in tissues where invasion and injury typically originate. After a brief refractory period, responding cells can resume functions as required in absence of further neural input.

Helps to explain some aspects of anti-inflammatory action
Aspirin and ibuprofin found to substantially increases vagus nerve activity.

Acupuncture, meditation, hypnosis, and relaxation therapies can stimulate vagus nerve.

Exercise raises vagus nerve activity and decreases cytokine levels.

Fish oil, soy oil, olive oil increases vagus nerve activity through cholecystokinin.1

1. Luyer, M.D., Greve, J.W., Hadfoune, M., Jacobs, J.A., Dejong, C.H. and Buurman, W.A. (2005) Nutritional stimulation of cholecystokinin receptors inhibits inflammation via the vagus nerve. J. Exp. Med. 202, 1023–1029

Main External Reference
Tracey K.J., 2007. Physiology and immunology of the cholinergic antiinflammatory pathway. J. Clin. Invest. 117: 289-296.