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Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin

Author

Listed:
  • Lyudmila V. Borovikova

    (The Picower Institute for Medical Research)

  • Svetlana Ivanova

    (The Picower Institute for Medical Research)

  • Minghuang Zhang

    (The Picower Institute for Medical Research)

  • Huan Yang

    (The Picower Institute for Medical Research)

  • Galina I. Botchkina

    (The Picower Institute for Medical Research)

  • Linda R. Watkins

    (University of Colorado)

  • Haichao Wang
  • Naji Abumrad

    (Department of Emergency Medicine
    North Shore University Hospital)

  • John W. Eaton

    (Department of Pediatrics Baylor College of Medicine)

  • Kevin J. Tracey

    (Department of Emergency Medicine
    North Shore University Hospital)

Abstract

Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. Endotoxin (lipopolysaccharide), produced by all gram-negative bacteria, activates macrophages to release cytokines that are potentially lethal1,2,3,4. The central nervous system regulates systemic inflammatory responses to endotoxin through humoral mechanisms5,6,7,8. Activation of afferent vagus nerve fibres by endotoxin or cytokines stimulates hypothalamic–pituitary–adrenal anti-inflammatory responses9,10,11. However, comparatively little is known about the role of efferent vagus nerve signalling in modulating inflammation. Here, we describe a previously unrecognized, parasympathetic anti-inflammatory pathway by which the brain modulates systemic inflammatory responses to endotoxin. Acetylcholine, the principle vagal neurotransmitter, significantly attenuated the release of cytokines (tumour necrosis factor (TNF), interleukin (IL)-1β, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures. Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.

Suggested Citation

  • Lyudmila V. Borovikova & Svetlana Ivanova & Minghuang Zhang & Huan Yang & Galina I. Botchkina & Linda R. Watkins & Haichao Wang & Naji Abumrad & John W. Eaton & Kevin J. Tracey, 2000. "Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin," Nature, Nature, vol. 405(6785), pages 458-462, May.
    • Handle: RePEc:nat:nature:v:405:y:2000:i:6785:d:10.1038_35013070
    DOI: 10.1038/35013070
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    Cited by:

    1. Claudio Bascour-Sandoval & Rubén Gajardo-Burgos & Claudio Muñoz-Poblete & Pablo Riedemann-González & Stephanie Erices-Salas & Agustín Martínez-Molina & Germán Gálvez-García, 2022. "Transcutaneous Vagal Stimulation in Knee Osteoarthritis (TRAVKO): Protocol of a Superiority, Outcome Assessor- and Participant-Blind, Randomised Controlled Trial," IJERPH, MDPI, vol. 20(1), pages 1-13, December.
    2. Ozlem Guzel & Ahmet Gulcubuk & Esma Yildar & Feraye Esen Gursel & Iraz Akis & Funda Bagcigil & Ozge Erdogan Bamac & Gulay Yuzbasioglu Ozturk & Bulent Ekiz, 2019. "Effects of antibiotic and intra-peritoneal ozone administration on proinflammatory cytokine formation, antioxidant levels and abdominal organ functions in the treatment of experimentally generated inf," Veterinární medicína, Czech Academy of Agricultural Sciences, vol. 64(8), pages 348-361.
    3. Carlota Saldanha & Ana Silva Herdade, 2018. "Erythrocyte Acetylcholinesterase is a Signaling Receptor," Novel Approaches in Drug Designing & Development, Juniper Publishers Inc., vol. 3(4), pages 77-80, January.
    4. Sarka Mala & Lucie Hoskovcova & Lucie Riedlbauchova & Tomas Nedelka & Maria Teresa Zanella, 2018. "Relationship Between Cardiac Autonomic Neuropathy and Atherosclerosis in Patients with Diabetes Mellitus," Current Research in Diabetes & Obesity Journal, Juniper Publishers Inc., vol. 9(1), pages 14-19, October.
    5. David Ojeda & Virginie Le Rolle & Hector M Romero-Ugalde & Clément Gallet & Jean-Luc Bonnet & Christine Henry & Alain Bel & Philippe Mabo & Guy Carrault & Alfredo I Hernández, 2016. "Sensitivity Analysis of Vagus Nerve Stimulation Parameters on Acute Cardiac Autonomic Responses: Chronotropic, Inotropic and Dromotropic Effects," PLOS ONE, Public Library of Science, vol. 11(9), pages 1-19, September.
    6. Ram B Singh & Shaw Watanabe & Duo Li & Teiji Nakamura & Lekh Raj Juneja & Toru Takahashi & Anuj Maheshwari & Narsingh Verma & Sanit Wichansawakun & Germaine Cornelissen & Agnieszka Wilczynska & Ibrahi, 2019. "Diet And Lifestyle Guidelines And Desirable Levels Of Risk Factors And Protective Factors For Prevention Of Dementia - A Scientific Statement From Joint Symposium Of Jaas And Apcns," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 17(3), pages 12844-12864, April.
    7. Gerald A Cheadle & Todd W Costantini & Nicole Lopez & Vishal Bansal & Brian P Eliceiri & Raul Coimbra, 2013. "Enteric Glia Cells Attenuate Cytomix-Induced Intestinal Epithelial Barrier Breakdown," PLOS ONE, Public Library of Science, vol. 8(7), pages 1-1, July.
    8. Fábio M de Castilho & Antonio Luiz P Ribeiro & José Luiz P da Silva & Vandack Nobre & Marcos R de Sousa, 2017. "Heart rate variability as predictor of mortality in sepsis: A prospective cohort study," PLOS ONE, Public Library of Science, vol. 12(6), pages 1-15, June.
    9. Lola Rueda Ruzafa & José Luis Cedillo & Arik J. Hone, 2021. "Nicotinic Acetylcholine Receptor Involvement in Inflammatory Bowel Disease and Interactions with Gut Microbiota," IJERPH, MDPI, vol. 18(3), pages 1-19, January.
    10. Fábio M de Castilho & Antonio Luiz P Ribeiro & Vandack Nobre & Guilherme Barros & Marcos R de Sousa, 2018. "Heart rate variability as predictor of mortality in sepsis: A systematic review," PLOS ONE, Public Library of Science, vol. 13(9), pages 1-13, September.
    11. Giorgio Noera & Alfio Bertolini, 2020. "Novel Treatments for Multiple Organ Failure- A Brief Account of Enthusiasms, Disappointments and Neglect," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 29(5), pages 22900-22906, August.
    12. Ewa Rudnicka-Drożak & Paulina Drożak & Grzegorz Mizerski & Tomasz Zaborowski & Barbara Ślusarska & Grzegorz Nowicki & Martyna Drożak, 2023. "Links between COVID-19 and Alzheimer’s Disease—What Do We Already Know?," IJERPH, MDPI, vol. 20(3), pages 1-15, January.
    13. Jong-Chan Youn & Hye Sun Lee & Suk-Won Choi & Seong-Woo Han & Kyu-Hyung Ryu & Eui-Cheol Shin & Seok-Min Kang, 2016. "Post-Exercise Heart Rate Recovery Independently Predicts Clinical Outcome in Patients with Acute Decompensated Heart Failure," PLOS ONE, Public Library of Science, vol. 11(5), pages 1-12, May.
    14. Jesus González-Rubio & Carmen Navarro-López & Elena López-Nájera & Ana López-Nájera & Lydia Jiménez-Díaz & Juan D. Navarro-López & Alberto Nájera, 2020. "A Systematic Review and Meta-Analysis of Hospitalised Current Smokers and COVID-19," IJERPH, MDPI, vol. 17(20), pages 1-16, October.
    15. Zheng-Liang Peng & Liang-Wei Huang & Jian Yin & Ke-Na Zhang & Kang Xiao & Guo-Zhong Qing, 2018. "Association between early serum cholinesterase activity and 30-day mortality in sepsis-3 patients: A retrospective cohort study," PLOS ONE, Public Library of Science, vol. 13(8), pages 1-14, August.
    16. Landau, E.R. & Raniti, M.B. & Blake, M. & Waloszek, J.M. & Blake, L. & Simmons, J.G. & Schwartz, O. & Murray, G. & Trinder, J. & Allen, N.B. & Byrne, M.L., 2021. "The ratio of morning cortisol to CRP prospectively predicts first-onset depression in at-risk adolescents," Social Science & Medicine, Elsevier, vol. 281(C).

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