Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis
Abstract
Physiological anti-inflammatory mechanisms can potentially be exploited for the treatment of inflammatory disorders. Here we report that the neurotransmitter acetylcholine inhibits HMGB1 release from human macrophages by signaling through a nicotinic acetylcholine receptor. Nicotine, a selective cholinergic agonist, is more efficient than acetylcholine and inhibits HMGB1 release induced by either endotoxin or tumor necrosis factor-alpha (TNF-alpha). Nicotinic stimulation prevents activation of the NF-kappaB pathway and inhibits HMGB1 secretion through a specific 'nicotinic anti-inflammatory pathway' that requires the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). In vivo, treatment with nicotine attenuates serum HMGB1 levels and improves survival in experimental models of sepsis, even when treatment is started after the onset of the disease. These results reveal acetylcholine as the first known physiological inhibitor of HMGB1 release from human macrophages and suggest that selective nicotinic agonists for the alpha7nAChR might have therapeutic potential for the treatment of sepsis.
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Macrophages and other cytokine-producing cells express acetylcholine receptors that transduce an intracellular signal inhibiting cytokine synthesis.
“Macrophages and other cytokine-producing cells express acetylcholine receptors (AChRs), which transduce an intracellular signal that inhibits cytokine synthesis (26,27).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [27]
Treatment of mice with nicotine significantly reduced serum levels of HMGB1 in a cecal perforation model of lethal peritonitis.
“Treatment of these mice with nicotine, a potent α7 nAChR agonist, significantly reduced serum levels of HMGB1, a cytokine mediator of lethality in this model (27).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [27]
Ligand-receptor interaction on cytokine-expressing cells culminates in decreased nuclear translocation of NF-κB and activation of STAT3 via phosphorylation by JAK2 recruited to the α7 nAChR.
“Ligand-receptor interaction on cytokine-expressing cells culminates in decreased nuclear translocation of NF-κB as well as activation of the transcription factor STAT3 via phosphorylation by JAK2, which is recruited to the α7 nAChR (Figure 3) (22,27).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [27]
The α7 subunit of the nicotinic AChR is the best characterized cholinergic receptor that suppresses cytokines.
“The best characterized of these cholinergic receptors that suppress cytokines is the α7 subunit of the nicotinic AChR (α7 nAChR).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [27]
The cholinergic antiinflammatory pathway can control cytokine responses even when the disease process is already established.
“Notably, nicotine administration did not begin until 24 hours after the onset of lethal peritonitis in this model, indicating that the cholinergic antiinflammatory pathway can control cytokine responses even when the disease process is already established (27).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [27]
α7 nAChR-dependent signals, which can be activated via vagus nerve stimulation, regulate cytokine production and the capacity for damage.
“Nonetheless, together the present results indicate that α7 nAChR-dependent signals, which can be activated via vagus nerve stimulation, regulate cytokine production and the capacity for damage.”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [27]
Vagus nerve stimulation or administration of α7 nAChR agonists inhibits TNF, IL-1, IL-6, IL-8, and HMGB1.
“Vagus nerve stimulation, or administration of α7 nAChR agonists, inhibits not only TNF but also IL-1, IL-6, IL-8, and highmobility group box 1 (HMGB1) (27).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [27]
Cholinergic signals derived from vagus nerve stimulation inhibit the release of TNF, IL-1, HMGB1, and other cytokines by transducing a cellular signal that inhibits the nuclear activity of NF-κB.
“Cholinergic signals derived from vagus nerve stimulation inhibit the release of TNF, IL-1, HMGB1, and other cytokines by transducing a cellular signal that inhibits the nuclear activity of NF-κB.”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [27]
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- Authors
- Wang, H., Liao, H., Ochani, M., Justiniani, M., Lin, X., Yang, L., Al-Abed, Y., Wang, H., Metz, C., Miller, E. J., Tracey, K. J., & Ulloa, L.
- Affiliations
- North Shore University Hospital (US)
- Corresponding author
- Ulloa, Luis
- ORCID
- Venue
- Nature Medicine
- Published
- 2004-10-24
- Volume
- 10
- Issue
- 11
- Pages
- 1216-1221
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2042821764
- Semantic Scholar
- fcef92fe7df0670524ba8a6beb63c9a4828e3e60
- Cited by
- 1,170
- References
- 49
- Citations by year
- 2026: 14 · 2025: 20 · 2024: 29 · 2023: 21 · 2022: 54 · 2021: 56 · 2020: 54 · 2019: 53 · 2018: 66 · 2017: 59 · 2016: 71 · 2015: 64 · 2014: 79 · 2013: 71 · 2012: 66
- FWCI
- 31.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- HMGB1, sepsis, acetylcholine, nicotinic acetylcholine receptors, alpha7 nicotinic acetylcholine receptor, nicotine, macrophages, endotoxin, TNF-α, NF-κB signaling, anti-inflammatory signaling, cholinergic agonists, survival
- MeSH terms
- Acetylcholine, Animals, Cecum, Fluorescent Antibody Technique, Humans, Inflammation, Lipopolysaccharides, Macrophages, Nicotine, Oligonucleotides, Receptors, Nicotinic, Neuroimmunomodulation, Signal Transduction, Sepsis, HMGB1 Protein, Mice, alpha7 Nicotinic Acetylcholine Receptor
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