Adenylyl cyclase 6 mediates inhibition of TNF in the inflammatory reflex

Laura Tarnawski, Colin Reardon, April S. Caravaca, Mauricio Rosas-Ballina, Michael W. Tusche, Anna R. Drake, La Queta K. Hudson, William M. Hanes, Jian Hua Li, William R. Parrish, Kaie Ojamaa, Yousef Al-Abed, Michael Faltys, Valentin A. Pavlov, Ulf Andersson, Sangeeta S. Chavan, Yaakov A. Levine, Tak W. Mak, Kevin J. Tracey, Peder S. Olofsson

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Macrophage cytokine production is regulated by neural signals, for example in the inflammatory reflex. Signals in the vagus and splenic nerves are relayed by choline acetyltransferase+ T cells that release acetylcholine, the cognate ligand for alpha7 nicotinic acetylcholine subunit-containing receptors (α7nAChR), and suppress TNF release in macrophages. Here, we observed that electrical vagus nerve stimulation with a duration of 0.1–60 s significantly reduced systemic TNF release in experimental endotoxemia. This suppression of TNF was sustained for more than 24 h, 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 1 h in vitro attenuated TNF production for up to 24 h in response to endotoxin. Pharmacological inhibition of adenylyl cyclase (AC) and knockdown of adenylyl cyclase 6 (AC6) or c-FOS abolished cholinergic suppression of endotoxin-induced TNF release. These findings indicate that action potentials in the inflammatory reflex trigger a change in macrophage behavior that requires AC and phosphorylation of the cAMP response element binding protein (CREB). These observations further our mechanistic understanding of neural regulation of inflammation and may have implications for development of bioelectronic medicine treatment of inflammatory diseases.

Original languageEnglish (US)
Article number2648
JournalFrontiers in Immunology
Volume9
Issue numberNOV
DOIs
StatePublished - Nov 27 2018

Fingerprint

Reflex
Macrophages
Adenylyl Cyclases
Endotoxins
Acetylcholine
Ligands
Vagus Nerve Stimulation
Cyclic AMP Response Element-Binding Protein
Endotoxemia
Vagus Nerve
Choline O-Acetyltransferase
Cholinergic Agents
Action Potentials
Phosphorylation
Medicine
adenylyl cyclase 6
Inhibition (Psychology)
Pharmacology
Cytokines
Inflammation

Keywords

  • Acetylcholine
  • Adenylyl cyclase 6
  • Choline acetyltransferase
  • Inflammatory reflex
  • Sustained TNF inhibition
  • Vagus nerve stimulation/VNS
  • Α7nAChR

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Tarnawski, L., Reardon, C., Caravaca, A. S., Rosas-Ballina, M., Tusche, M. W., Drake, A. R., ... Olofsson, P. S. (2018). Adenylyl cyclase 6 mediates inhibition of TNF in the inflammatory reflex. Frontiers in Immunology, 9(NOV), [2648]. https://doi.org/10.3389/fimmu.2018.02648

Adenylyl cyclase 6 mediates inhibition of TNF in the inflammatory reflex. / Tarnawski, Laura; Reardon, Colin; Caravaca, April S.; Rosas-Ballina, Mauricio; Tusche, Michael W.; Drake, Anna R.; Hudson, La Queta K.; Hanes, William M.; Li, Jian Hua; Parrish, William R.; Ojamaa, Kaie; Al-Abed, Yousef; Faltys, Michael; Pavlov, Valentin A.; Andersson, Ulf; Chavan, Sangeeta S.; Levine, Yaakov A.; Mak, Tak W.; Tracey, Kevin J.; Olofsson, Peder S.

In: Frontiers in Immunology, Vol. 9, No. NOV, 2648, 27.11.2018.

Research output: Contribution to journalArticle

Tarnawski, L, Reardon, C, Caravaca, AS, Rosas-Ballina, M, Tusche, MW, Drake, AR, Hudson, LQK, Hanes, WM, Li, JH, Parrish, WR, Ojamaa, K, Al-Abed, Y, Faltys, M, Pavlov, VA, Andersson, U, Chavan, SS, Levine, YA, Mak, TW, Tracey, KJ & Olofsson, PS 2018, 'Adenylyl cyclase 6 mediates inhibition of TNF in the inflammatory reflex', Frontiers in Immunology, vol. 9, no. NOV, 2648. https://doi.org/10.3389/fimmu.2018.02648
Tarnawski L, Reardon C, Caravaca AS, Rosas-Ballina M, Tusche MW, Drake AR et al. Adenylyl cyclase 6 mediates inhibition of TNF in the inflammatory reflex. Frontiers in Immunology. 2018 Nov 27;9(NOV). 2648. https://doi.org/10.3389/fimmu.2018.02648
Tarnawski, Laura ; Reardon, Colin ; Caravaca, April S. ; Rosas-Ballina, Mauricio ; Tusche, Michael W. ; Drake, Anna R. ; Hudson, La Queta K. ; Hanes, William M. ; Li, Jian Hua ; Parrish, William R. ; Ojamaa, Kaie ; Al-Abed, Yousef ; Faltys, Michael ; Pavlov, Valentin A. ; Andersson, Ulf ; Chavan, Sangeeta S. ; Levine, Yaakov A. ; Mak, Tak W. ; Tracey, Kevin J. ; Olofsson, Peder S. / Adenylyl cyclase 6 mediates inhibition of TNF in the inflammatory reflex. In: Frontiers in Immunology. 2018 ; Vol. 9, No. NOV.
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AU - Hanes, William M.

AU - Li, Jian Hua

AU - Parrish, William R.

AU - Ojamaa, Kaie

AU - Al-Abed, Yousef

AU - Faltys, Michael

AU - Pavlov, Valentin A.

AU - Andersson, Ulf

AU - Chavan, Sangeeta S.

AU - Levine, Yaakov A.

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