Neuroimmune nexus in the pathophysiology and therapy of inflammatory disorders: Role of α7 nicotinic acetylcholine receptors

Keever, Kasey R.; Yakubenko, Valentin P.; Hoover, Donald B.

doi:10.1016/j.phrs.2023.106758

Cited by 83Vagus Nerve Stimulation ResearchNicotinic Acetylcholine Receptors StudyNeuroinflammation and Neurodegeneration Mechanisms

Neuroimmune nexus in the pathophysiology and therapy of inflammatory disorders: Role of α7 nicotinic acetylcholine receptors

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Keever, Kasey R., Yakubenko, Valentin P., Hoover, Donald B.·2023·Pharmacological Research

DOI 10.1016/j.phrs.2023.106758PMC PMC13134767

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Abstract

The α7-nicotinic acetylcholine receptor (α7nAChR) is a key protein in the cholinergic anti-inflammatory pathway (CAP) that links the nervous and immune systems. Initially, the pathway was discovered based on the observation that vagal nerve stimulation (VNS) reduced the systemic inflammatory response in septic animals. Subsequent studies form a foundation for the leading hypothesis about the central role of the spleen in CAP activation. VNS evokes noradrenergic stimulation of ACh release from T cells in the spleen, which in turn activates α7nAChRs on the surface of macrophages. α7nAChR-mediated signaling in macrophages reduces inflammatory cytokine secretion and modifies apoptosis, proliferation, and macrophage polarization, eventually reducing the systemic inflammatory response. A protective role of the CAP has been demonstrated in preclinical studies for multiple diseases including sepsis, metabolic disease, cardiovascular diseases, arthritis, Crohn's disease, ulcerative colitis, endometriosis, and potentially COVID-19, sparking interest in using bioelectronic and pharmacological approaches to target α7nAChRs for treating inflammatory conditions in patients. Despite a keen interest, many aspects of the cholinergic pathway are still unknown. α7nAChRs are expressed on many other subsets of immune cells that can affect the development of inflammation differently. There are also other sources of ACh that modify immune cell functions. How the interplay of ACh and α7nAChR on different cells and in various tissues contributes to the anti-inflammatory responses requires additional study. This review provides an update on basic and translational studies of the CAP in inflammatory diseases, the relevant pharmacology of α7nAChR-activated drugs and raises some questions that require further investigation.

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Expression or downstream signaling (e.g., JAK2/STAT3) of the α7 nicotinic acetylcholine receptor (α7nAChR) is impaired in the inflammatory milieu, preventing ACh from effectively inhibiting NF-κB nuclear translocation and pro-inflammatory factor transcription.
“Expression or downstream signaling (e.g., JAK2/STAT3) of its key receptor, the α7 nicotinic acetylcholine receptor (α7nAChR), is impaired in the inflammatory milieu, preventing ACh from effectively inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) nuclear translocation and pro-inflammatory factor transcription [8].”
From Research Advances in the Pathogenesis of Sepsis-Associated Encephalopathy (2026) · cites this paper as [8]
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Ultrasound Neuromodulation of the Spleen Has Time-Dependent Anti-Inflammatory Effect in a Pneumonia Model
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Tropisetron Attenuates Cardiac Injury in a Rat Trauma–Hemorrhage Model
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Impact of Peripheral α7-Nicotinic Acetylcholine Receptors on Cardioprotective Effects of Donepezil in Chronic Heart Failure Rats
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The Cholinergic Drug Pyridostigmine Alleviates Inflammation During LPS-Induced Acute Respiratory Distress Syndrome
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Association Between Cholinesterase Inhibitors and New-Onset Heart Failure in Patients With Alzheimer's Disease: A Nationwide Propensity Score Matching Study
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The Constitutive Lack of α7 Nicotinic Receptor Leads to Metabolic Disorders in Mouse
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Varenicline aggravates plaque formation through α7 nicotinic acetylcholine receptors in ApoE KO mice
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Cynandione A and PHA-543613 inhibit inflammation and stimulate macrophageal IL-10 expression following α7 nAChR activation
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ICH3, a selective alpha7 nicotinic acetylcholine receptor agonist, modulates adipocyte inflammation associated with obesity
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Donepezil protects glycerol-induced acute renal failure through the cholinergic anti-inflammatory and nitric oxide pathway in rats
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Varenicline enhances oxidized LDL uptake by increasing expression of LOX-1 and CD36 scavenger receptors through α7 nAChR in macrophages
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Decreased α7nAChR mRNA levels in peripheral blood monocytes are associated with enhanced inflammatory cytokine production in patients with lupus nephritis
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The Positive Allosteric Modulation of alpha7-Nicotinic Cholinergic Receptors by GAT107 Increases Bacterial Lung Clearance in Hyperoxic Mice by Decreasing Oxidative Stress in Macrophages
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Activation of α7 nicotinic acetylcholine receptor retards the development of endometriosis
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Non-pharmacologic autonomic neuromodulation for treatment of heart failure: A systematic review and meta-analysis of randomized controlled trials
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Tropisetron Preconditioning Decreases Myocardial Biomarkers in Patients Undergoing Heart Valve Replacement Surgery
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[107]Su X, Matthay MA, Malik AB, Requisite role of the cholinergic alpha7 nicotinic acetylcholine receptor pathway in suppressing Gram-negative sepsis-induced acute lung inflammatory injury, J Immunol. 184 (2010) 401– 410. 10.4049/jimmunol.0901808. 19949071 PMC2877486 · DOI
[181]Barrish J, Carter P, Cheng P, Zahler R, Accounts in Drug Discovery: Case Studies in Medicinal Chemistry, eBook, Cambridge: Royal Society of Chemistry, 2010.

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Authors: Keever, K. R., Yakubenko, V. P., & Hoover, D. B.
Affiliations: East Tennessee State University (US)
Corresponding author: Hoover, Donald B.
ORCID: Keever, Kasey R.
Yakubenko, Valentin P.
Hoover, Donald B.
Venue: Pharmacological Research
Publisher: Elsevier BV
Published: 2023-05
Volume: 191
Pages: 106758
ISSN: 1043-6618 (ISSN-L)
DOI: 10.1016/j.phrs.2023.106758
PMC: PMC13134767
OpenAlex: W4362636707
Cited by: 82
References: 178
Citations by year: 2026: 37 · 2025: 25 · 2024: 18 · 2023: 2
FWCI: 2.13
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Pharmacological Research (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
PubMed Central (submittedVersion)
Funders: National Institutes of Health
National Heart, Lung, and Blood Institute (R15 HL157836-01A1)
East Tennessee State University James H Quillen College of Medicine
Topics: Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: alpha7 nicotinic acetylcholine receptor, cholinergic anti-inflammatory pathway, neuroimmune interactions, vagus nerve stimulation, macrophage polarization, sepsis, inflammatory cytokines, bioelectronic medicine, anti-inflammatory agents, autoimmune disease, COVID-19 pandemic
MeSH terms: COVID-19, Animals, Female, Inflammation, Macrophages, Receptors, Nicotinic, Systemic Inflammatory Response Syndrome, alpha7 Nicotinic Acetylcholine Receptor

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Neuroimmune nexus in the pathophysiology and therapy of inflammatory disorders: Role of α7 nicotinic acetylcholine receptors

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