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Cited by 683Vagus Nerve Stimulation ResearchCancer, Stress, Anesthesia, and Immune ResponseHeart Rate Variability and Autonomic Control

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Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis

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Huston, Jared M., Ochani, Mahendar, Rosas-Ballina, Mauricio, Liao, Hong, Ochani, Kanta, Pavlov, Valentin A., Gallowitsch-Puerta, Margot, Ashok, Mala, Czura, Christopher J., Foxwell, Brian, Tracey, Kevin J., Ulloa, Luis·2006·The Journal of Experimental Medicine
DOI 10.1084/jem.20052362PMC PMC2118357
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Abstract

The innate immune system protects against infection and tissue injury through the specialized organs of the reticuloendothelial system, including the lungs, liver, and spleen. The central nervous system regulates innate immune responses via the vagus nerve, a mechanism termed the cholinergic antiinflammatory pathway. Vagus nerve stimulation inhibits proinflammatory cytokine production by signaling through the α7 nicotinic acetylcholine receptor subunit. Previously, the functional relationship between the cholinergic antiinflammatory pathway and the reticuloendothelial system was unknown. Here we show that vagus nerve stimulation fails to inhibit tumor necrosis factor (TNF) production in splenectomized animals during lethal endotoxemia. Selective lesioning of the common celiac nerve abolishes TNF suppression by vagus nerve stimulation, suggesting that the cholinergic pathway is functionally hard wired to the spleen via this branch of the vagus nerve. Administration of nicotine, an α7 agonist that mimics vagus nerve stimulation, increases proinflammatory cytokine production and lethality from polymicrobial sepsis in splenectomized mice, indicating that the spleen is critical to the protective response of the cholinergic pathway. These results reveal a specific, physiological connection between the nervous and innate immune systems that may be exploited through either electrical vagus nerve stimulation or administration of α7 agonists to inhibit proinflammatory cytokine production during infection and tissue injury.

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Figure 1. Effect of vagus nerve stimulation on organ-specific TNF production in lethal endotoxemia. (A) Lewis rats received electrical vagus nerve stimulation or sham stimulation 10 min before and 10 min after an LD50 dose of endotoxin (15 mg/kg, i.v.). Organs were collected after 90 min, and TNF was normalized to the amount of protein per organ (n = 4–8 per group). *, P < 0.01 versus control; **, P < 0.05 versus LPS; ***, P < 0.01 versus LPS. (B) Effect of vagus nerve stimulation on hepatic and splenic TNF mRNA levels in lethal endotoxemia. Lewis rats received electrical vagus nerve stimulation or sham stimulation 10 min before and 10 min after endotoxin injection (15 mg/kg, i.v.). Organs were collected after 60 min, and TNF mRNA expression was determined by quantitative RT-PCR (n = 4–8 per group). *, P < 0.01 versus control; **, P < 0.05 versus LPS.
Figure 1. Effect of vagus nerve stimulation on organ-specific TNF production in lethal endotoxemia. (A) Lewis rats received electrical vagus nerve stimulation or sham stimulation 10 min before and 10 min after an LD50 dose of endotoxin (15 mg/kg, i.v.). Organs were collected after 90 min, and TNF was normalized to the amount of protein per organ (n = 4–8 per group). *, P < 0.01 versus control; **, P < 0.05 versus LPS; ***, P < 0.01 versus LPS. (B) Effect of vagus nerve stimulation on hepatic and splenic TNF mRNA levels in lethal endotoxemia. Lewis rats received electrical vagus nerve stimulation or sham stimulation 10 min before and 10 min after endotoxin injection (15 mg/kg, i.v.). Organs were collected after 60 min, and TNF mRNA expression was determined by quantitative RT-PCR (n = 4–8 per group). *, P < 0.01 versus control; **, P < 0.05 versus LPS.CC BY-NC-SA · PubMed Central
Figure 2. Vagus nerve stimulation fails to inhibit systemic TNF production in splenectomized animals. (A) Lewis rats underwent splenectomy or sham surgery, and 3 d later they were injected with endotoxin (15 mg/kg, i.v.) and treated with vagus nerve stimulation or sham stimulation. Serum was collected after 90 min. Data are presented as mean ± SEM (n = 6 per group). *, P < 0.01 versus control; **, P < 0.05 versus LPS. (B and C) The common celiac vagus branches mediate the TNF-suppressing effect of vagus nerve stimulation. Selective subdiaphragmatic ventral vagotomy (VVgx) or common celiac branch vagotomy (CVgx) was performed before endotoxin administration (15 mg/kg, i.v.) and vagus nerve stimulation or sham stimulation. TNF concentrations in rat spleen and serum were determined after 90 min. Data are presented as mean ± SEM (n = 5 per group). *, P < 0.01 versus control; **, P < 0.05 versus LPS.
Figure 2. Vagus nerve stimulation fails to inhibit systemic TNF production in splenectomized animals. (A) Lewis rats underwent splenectomy or sham surgery, and 3 d later they were injected with endotoxin (15 mg/kg, i.v.) and treated with vagus nerve stimulation or sham stimulation. Serum was collected after 90 min. Data are presented as mean ± SEM (n = 6 per group). *, P < 0.01 versus control; **, P < 0.05 versus LPS. (B and C) The common celiac vagus branches mediate the TNF-suppressing effect of vagus nerve stimulation. Selective subdiaphragmatic ventral vagotomy (VVgx) or common celiac branch vagotomy (CVgx) was performed before endotoxin administration (15 mg/kg, i.v.) and vagus nerve stimulation or sham stimulation. TNF concentrations in rat spleen and serum were determined after 90 min. Data are presented as mean ± SEM (n = 5 per group). *, P < 0.01 versus control; **, P < 0.05 versus LPS.CC BY-NC-SA · PubMed Central
Figure 3. Vagus nerve regulation of TNF production in the spleen requires the α7nAChR. (A and B) Wild-type (+/+) and α7nAChR-deficient mice (−/−) received vagus nerve stimulation before endotoxin administration (7.5 mg/kg, i.p.). TNF concentrations were measured in the spleen and serum after 90 min. Data are presented as mean ± SEM (n = 10 per group). **, P < 0.05. (C) Regulation of splenocyte TNF production by acetylcholine requires the α7nAChR. Primary splenocyte cultures from wild-type (+/+) and α7nAChR-deficient mice (−/−) were treated with endotoxin in the presence of acetylcholine. Data are presented as mean ± SEM. **, P < 0.05. (D) Acetylcholine does not affect splenocyte TGF-β production. Primary splenocyte cultures from wild-type (+/+) and α7nAChR-deficient mice (−/−) were treated with endotoxin in the presence of acetylcholine. Data are presented as mean ± SEM.
Figure 3. Vagus nerve regulation of TNF production in the spleen requires the α7nAChR. (A and B) Wild-type (+/+) and α7nAChR-deficient mice (−/−) received vagus nerve stimulation before endotoxin administration (7.5 mg/kg, i.p.). TNF concentrations were measured in the spleen and serum after 90 min. Data are presented as mean ± SEM (n = 10 per group). **, P < 0.05. (C) Regulation of splenocyte TNF production by acetylcholine requires the α7nAChR. Primary splenocyte cultures from wild-type (+/+) and α7nAChR-deficient mice (−/−) were treated with endotoxin in the presence of acetylcholine. Data are presented as mean ± SEM. **, P < 0.05. (D) Acetylcholine does not affect splenocyte TGF-β production. Primary splenocyte cultures from wild-type (+/+) and α7nAChR-deficient mice (−/−) were treated with endotoxin in the presence of acetylcholine. Data are presented as mean ± SEM.CC BY-NC-SA · PubMed Central
Figure 4. Nicotine worsens survival in splenectomized animals with lethal polymicrobial sepsis. (A) BALB/c mice were subjected to splenectomy before cecal ligation and puncture (CLP). Nicotine (400 μg/kg, i.p.) or vehicle treatment began 24 h later and was administered twice a day for 3 d. Data are shown as percent of animals surviving (n > 20 per group). *, P < 0.05 versus control; **, P < 0.05 versus CLP. (B) Nicotine increases serum HMGB1 levels in splenectomized animals. BALB/c mice were subjected to splenectomy before cecal ligation and puncture, and nicotine (400 μg/kg, i.p.) or vehicle treatment began 24 h after surgery. Blood was collected 44 h after surgery, and serum HMGB1 concentration was determined by Western blot and densitometric analysis. Data are presented as mean ± SEM (n > 8 per group). **, P < 0.05.
Figure 4. Nicotine worsens survival in splenectomized animals with lethal polymicrobial sepsis. (A) BALB/c mice were subjected to splenectomy before cecal ligation and puncture (CLP). Nicotine (400 μg/kg, i.p.) or vehicle treatment began 24 h later and was administered twice a day for 3 d. Data are shown as percent of animals surviving (n > 20 per group). *, P < 0.05 versus control; **, P < 0.05 versus CLP. (B) Nicotine increases serum HMGB1 levels in splenectomized animals. BALB/c mice were subjected to splenectomy before cecal ligation and puncture, and nicotine (400 μg/kg, i.p.) or vehicle treatment began 24 h after surgery. Blood was collected 44 h after surgery, and serum HMGB1 concentration was determined by Western blot and densitometric analysis. Data are presented as mean ± SEM (n > 8 per group). **, P < 0.05.CC BY-NC-SA · PubMed Central

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  1. 1998, Am. J. Physiol., 275, R63

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Metadata

Authors
Huston, J. M., Ochani, M., Rosas-Ballina, M., Liao, H., Ochani, K., Pavlov, V. A., Gallowitsch-Puerta, M., Ashok, M., Czura, C. J., Foxwell, B., Tracey, K. J., & Ulloa, L.
Affiliations
  • 1Laboratory of Biomedical Science
  • Imperial College London (GB)
  • Northwell Health (US)
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2006-06-19
Volume
203
Issue
7
Pages
1623-1628
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20052362
PMC
PMC2118357
OpenAlex
W2154170498
Cited by
683
References
30
Citations by year
2026: 25 · 2025: 22 · 2024: 37 · 2023: 32 · 2022: 50 · 2021: 51 · 2020: 37 · 2019: 44 · 2018: 33 · 2017: 40 · 2016: 29 · 2015: 31 · 2014: 36 · 2013: 25 · 2012: 39
FWCI
18.41
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • Defense Advanced Research Projects Agency
  • Advanced Research Projects Agency
  • National Institute of General Medical Sciences (R01GM057226)
  • National Center for Research Resources (M01RR018535)
Topics
  • Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Stress, Anesthesia, and Immune Response
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
Keywords
splenectomy, cholinergic anti-inflammatory pathway, vagus nerve stimulation, alpha7 nicotinic acetylcholine receptor, endotoxemia, polymicrobial sepsis, TNF-α, reticuloendothelial system, spleen, nicotine, inflammatory cytokines, neuroimmune regulation
MeSH terms
Acetylcholine, Animals, Female, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Rats, Inbred Lew, Splenectomy, Signal Transduction, Mice, Knockout, Sepsis, Endotoxemia, Mice, Rats

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