Whole blood cytokine attenuation by cholinergic agonists ex vivo and relationship to vagus nerve activity in rheumatoid arthritis
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Abstract. Bruchfeld A, Goldstein RS, Chavan S, Patel NB, Rosas‐Ballina M, Kohn N, Qureshi AR, Tracey KJ. (Karolinska Institute, Stockholm, Sweden; The Feinstein Institute for Medical Research, North Shore University Hospital‐LIJ Health System, Manhasset, NY, USA; and Karolinska Institute, Stockholm, Sweden) Whole blood cytokine attenuation by cholinergic agonists ex vivo and relationship to vagus nerve activity in rheumatoid arthritis. J Intern Med 2010; 268:94–101. Objective. The central nervous system regulates innate immunity in part via the cholinergic anti‐inflammatory pathway, a neural circuit that transmits signals in the vagus nerve that suppress pro‐inflammatory cytokine production by an α‐7 nicotinic acetylcholine receptors (α7nAChR) dependent mechanism. Vagus nerve activity is significantly suppressed in patients with autoimmune diseases, including rheumatoid arthritis (RA). It has been suggested that stimulating the cholinergic anti‐inflammatory pathway may be beneficial to patients, but it remains theoretically possible that chronic deficiencies in this pathway will render these approaches ineffective. Methods. Here we addressed the hypothesis that inflammatory cells from RA patients can respond to cholinergic agonists with reduced cytokine production in the setting of reduced vagus nerve activity. Results. Measurement of RR interval variability (heart rate variability, HRV), in RA patients (n = 13) and healthy controls (n = 10) revealed that vagus nerve activity was significantly depressed in patients. Whole blood cultures stimulated by exposure to endotoxin produced significantly less tumour necrosis factor in samples from RA patients as compared to healthy controls. Addition of cholinergic agonists (nicotine and GTS‐21) to the stimulated whole blood cultures however significantly suppressed cytokine production to a similar extent in patients and healthy controls. Conclusion. These findings suggest that it is possible to pharmacologically target the α7nAChR dependent control of cytokine release in RA patients with suppressed vagus nerve activity. As α7nAChR agonists ameliorate the clinical course of collagen induced arthritis in animals, it may be possible in the future to explore whether α7nAChR agonists can improve clinical activity in RA patients.
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Chronic inflammation such as in rheumatoid arthritis is accompanied by vagal hypoactivity and sympathetic hyperactivity.
“However, chronic inflammation such as in RA is accompanied by vagal hypoactivity and sympathetic hyperactivity [108-110].”
From Interaction of the endocrine system with inflammation: a function of energy and volume regulation (2014) · cites this paper as [109]
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- Authors
- Bruchfeld, A., Goldstein, R. S., Chavan, S., Patel, N. B., Rosas‐Ballina, M., Kohn, N., Qureshi, A. R., & Tracey, K. J.
- Affiliations
- Karolinska Institutet (SE)
- Feinstein Institute for Medical Research (US)
- Corresponding author
- Bruchfeld, A.
- Venue
- Journal of Internal Medicine
- Publisher
- Wiley
- Published
- 2010-06-09
- Volume
- 268
- Issue
- 1
- Pages
- 94-101
- ISSN
- 0954-6820 (ISSN-L)
- 1365-2796
- PMC
- PMC2937357
- OpenAlex
- W2007436570
- Cited by
- 99
- References
- 35
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 1 · 2022: 3 · 2021: 6 · 2020: 8 · 2019: 4 · 2018: 5 · 2017: 6 · 2016: 13 · 2015: 7 · 2014: 11 · 2013: 3 · 2012: 10
- FWCI
- 5.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Internal Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01-GM57726, R01GM62508, R01GM057226, R01GM062508)
- National Center for Research Resources (M01RR018535)
- Topics
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- rheumatoid arthritis, cholinergic anti-inflammatory pathway, vagus nerve activity, alpha7 nicotinic acetylcholine receptor, cholinergic agonists, GTS-21, nicotine, cytokine production, TNF-α, heart rate variability, endotoxin stimulation, whole blood culture, innate immunity
- MeSH terms
- Adult, Aged, Arthritis, Rheumatoid, Benzylidene Compounds, C-Reactive Protein, Dose-Response Relationship, Immunologic, Female, Heart Rate, Humans, Lipopolysaccharides, Male, Middle Aged, Nicotine, Prospective Studies, Pyridines, Receptors, Nicotinic, Tumor Necrosis Factor-alpha, Vagus Nerve, Case-Control Studies, Cytokines, Cholinergic Agonists, HMGB1 Protein, Tissue Culture Techniques, alpha7 Nicotinic Acetylcholine Receptor
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