key: cord-0773681-1f8m61bm
authors: Mehranfard, Danial; Speth, Robert C.
title: Cholinergic anti-inflammatory pathway and COVID-19
date: 2022-01-22
journal: Bioimpacts
DOI: 10.34172/bi.2022.23980
sha: 509a7e568561f6fc870c1d8829e0aef7614c0323
doc_id: 773681
cord_uid: 1f8m61bm

[Image: see text] The cholinergic anti-inflammatory pathway (CAP) first described by Wang et al, 2003 has contemporary interest arising from the COVID-19 pandemic. While tobacco smoking has been considered an aggravating factor in the severity of COVID-19 infections, it has been suggested by some that the nicotine derived from tobacco could lessen the severity of COVID-19 infections. This spotlight briefly describes the CAP and its potential role as a therapeutic target for the treatment of COVID-19 infections using vagus nerve stimulation or selective alpha7 nicotinic acetylcholine receptor agonists.

BioImpacts, 2022, 12(2), 171-174 172 neurosurgical intervention which is approved by the FDA for the treatment of depression and epilepsy in patients >12 years of age 20 ; while transcutaneous vagus nerve stimulation (tVNS) of the auricular branch of the vagus nerve is suggested to be a non-invasive alternative means of vagal stimulation. 21 There are several ongoing clinical trials to assess the tVNS impact on different conditions such as stress response in major depression (NCT04448327), and pediatric inflammatory bowel disease (NCT03863704). Of note, there is an ongoing clinical trial to investigate whether transcutaneous electrical stimulation of the auricular branch of the vagus nerve will decrease the proinflammatory cytokine response in healthy individuals (NCT02910973).

Another type of non-invasive vagus nerve stimulation (NVNS) device, "gammaCore Sapphire TM CV" developed by electroCore, Inc., which fits onto the neck and sends pulses to the vagus nerve, has been granted emergency use authorization (EUA) for the treatment of COVID-19 associated dyspnea (https://www.fda.gov/media/139968/ download; accessed July 19, 2021).

Acetylcholine is primarily produced by neurons for use as a neurotransmitter, but non-neuronal cells, including T cells in the spleen, can also synthesize ACh. After splenectomy, vagus nerve stimulation is no longer able to reduce inflammation, therefore the spleen is vital for the CAP response. [22] [23] [24] [25] As shown in Fig. 1 , following vagal stimulation, the anti-inflammatory reflex travels through the sympathetic splenic nerve to the spleen. The splenic nerve, which uses norepinephrine as its neurotransmitter, activates beta-2 adrenergic receptors (β2AR) on acetylcholine-producing T cells (choline acetyltransferase positive T-cells (CHAT+)). This stimulates them to secrete ACh in the spleen, establishing an anti-inflammatory response through activation of the α7nAChR on macrophages, 13 inhibiting their secretion of proinflammatory cytokines. 9, 26, 27 Of note, this anti-inflammatory effect is not limited to macrophages in the spleen. As shown in Fig. 1 , the innervation of vagus nerve into the other organs such as lungs and the gastrointestinal tract can exert a local anti-inflammatory effect. 28, 29 Nonetheless, the spleen is the efferent vagus nerve main targeted organ for the antiinflammatory effect. 24, 25 Concluding remarks: CAP and COVID-19 Autopsies of COVID-19 patients show a high infiltration of macrophages within the bronchopneumonia area. 30 Furthermore, ACE2 expressing macrophages containing SARS-CoV-2 nucleoprotein antigen densely infiltrate the lymph nodes and spleen of COVID-19 patients, causing significant interlukin-6 (IL-6) production. 31 In severe Fig. 1 . The cholinergic anti-inflammatory pathway (CAP) exerts its anti-inflammatory effect via efferent vagus nerve stimulation. The CAP then branches off in 3 directions: some vagal fibers innervate the celiac ganglion where they synapse with sympathetic neurons which project to the spleen where they innervate ACh producing T cells. The T cells then release ACh that binds to α7nAChR on macrophages. Activation of the α7nAChR on macrophages inhibits the synthesis and release of proinflammatory cytokines from the macrophages, altering them to the M 2 anti-inflammatory phenotype. The second branch of the CAP involves vagal efferents that innervate lung tissue, releasing ACh that directly activates α7nAChR on alveolar macrophages, again converting them to the M 2 anti-inflammatory phenotype. The third branch of the CAP involves vagal efferents that activate post-ganglionic parasympathetic enteric neurons in the gut, which release ACh that activates α7nAChR on resident macrophages in the gut again converting them to the M 2 anti-inflammatory phenotype. The effect of the CAP can be mimicked with pharmacological administration of selective α7nAChR agonists (depicted by the hypodermic needle). COVID-19 cases, substantial serum IL-6 elevation has been observed. 32 The high production of IL-6, together with the macrophage activation syndrome, 33 may explain the high serum level of C-reactive protein, 34 which is normally undetectable in viral infections. Therefore, macrophage activation may be an exacerbating factor for severe COVID-19 infection, producing proinflammatory cytokines and contributing to the cytokine storm. 31, 35 Anti-IL-6 or anti-IL-1 treatment of COVID-19 patients significantly improved patient symptoms. 33, [36] [37] [38] [39] Of note, a recent study has shown that vagus nerve stimulation inhibits the acute respiratory distress syndrome inflammatory response through activation of the α7nAChR, via the CAP. 14 Therefore, activation of the CAP through vagus nerve stimulation or pharmacological activation through selective α7nAChR agonists, may be a possible adjunctive therapy to ameliorate severe inflammation in COVID-19 patients by inhibiting production and release of proinflammatory cytokines by macrophages, thereby reducing the cytokine storm that is a major contributor to COVID-19 morbidity, without causing systemic effects of nicotinic cholinergic receptor stimulation.

None.

Not applicable.

None delared.

Authors' contribution DM and RCS drafted the article, designed the figure, and approved the version to be published.

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