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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2018.02648

Adenylyl Cyclase 6 mediates inhibition of TNF in the inflammatory reflex

 Laura Tarnawski1*,  Colin Reardon2, April S. Caravaca1,  Mauricio Rosas-Ballina3, Michael W. Tusche4, Anna R. Drake5, LaQueta K. Hudson3,  William Hanes3, Jian Hua Li3,  William R. Parrish3,  Kaie Ojamaa6, Yousef Al-Abed3, Michael Faltys5,  Valentin A. Pavlov3,  Ulf Andersson3, 7,  Sangeeta S. Chavan3,  Yaakov A. Levine5, Tak W. Mak4, Kevin J. Tracey3 and  Peder S. Olofsson1, 3
  • 1Karolinska Institutet (KI), Sweden
  • 2University of California, Davis, United States
  • 3Feinstein Institute for Medical Research, United States
  • 4Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Canada
  • 5SetPoint Medical, Inc., United States
  • 6Department of Biological Sciences, New York City College of Technology, United States
  • 7Department of Women's and Children's Health , Karolinska Institute (KI), Sweden

Macrophage cytokine production is reflexively mediated by neural circuits. One example is the inflammatory reflex, defined by electrical signals traveling in the vagus nerve and signaling through splenic choline acetyltransferase+ T cells. Lymphocyte acetylcholine is the ligand for alpha7 nicotinic acetylcholine receptors (α7nAChR) on macrophages that suppress TNF release. Here, we observed that electrical vagus nerve stimulation of the inflammatory reflex with a duration of 0.1s - 60s significantly reduced systemic TNF release in endotoxemia. This suppression of TNF was sustained for more than 24 hours, but abolished in mice deficient in the α7nAChR subunit. Exposure of primary human macrophages and murine RAW 264.7 macrophage-like cells to selective ligands for α7nAChR for one hour in vitro attenuated TNF production for up to 24 hours in response to endotoxin. Pharmacological inhibition of adenylyl cyclase (AC) and knockdown of adenylyl cyclase 6 (AC6) or c-FOS abolished cholinergic mediated suppression of endotoxin-induced TNF release. These findings indicate that action potentials in the inflammatory reflex trigger an extended change in macrophage activation behavior that requires AC and phosphorylation of cAMP response element binding protein (CREB). This has significant implications for mechanisms of bioelectronic therapies to treat inflammatory diseases.

Keywords: Inflammatory reflex, Choline acetyltransferase (ChAT), Acetylcholine (ACh +), Adenylyl Cyclase 6 , α7nAChR, Sustained TNF inhibition, Vagus nerve stimulation or VNS

Received: 12 Sep 2018; Accepted: 26 Oct 2018.

Edited by:

Christoph Thiemermann, Queen Mary University of London, United Kingdom

Reviewed by:

Sergio I. Valdés-Ferrer, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico
Sina M. Coldewey, Universitätsklinikum Jena, Germany  

Copyright: © 2018 Tarnawski, Reardon, Caravaca, Rosas-Ballina, Tusche, Drake, Hudson, Hanes, Li, Parrish, Ojamaa, Al-Abed, Faltys, Pavlov, Andersson, Chavan, Levine, Mak, Tracey and Olofsson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Laura Tarnawski, Karolinska Institutet (KI), Solna, Sweden,