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Article: Adenylyl cyclase 6 mediates inhibition of TNF in the inflammatory reflex

TitleAdenylyl cyclase 6 mediates inhibition of TNF in the inflammatory reflex
Authors
KeywordsAdenylyl cyclase 6
Acetylcholine
Α7nAChR
Vagus nerve stimulation/VNS
Inflammatory reflex
Choline acetyltransferase
Sustained TNF inhibition
Issue Date2018
Citation
Frontiers in Immunology, 2018, v. 9, article no. 2648 How to Cite?
AbstractMacrophage 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.
Persistent Identifierhttp://hdl.handle.net/10722/292093
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorTarnawski, Laura-
dc.contributor.authorReardon, Colin-
dc.contributor.authorCaravaca, April S.-
dc.contributor.authorRosas-Ballina, Mauricio-
dc.contributor.authorTusche, Michael W.-
dc.contributor.authorDrake, Anna R.-
dc.contributor.authorHudson, La Queta K.-
dc.contributor.authorHanes, William M.-
dc.contributor.authorLi, Jian Hua-
dc.contributor.authorParrish, William R.-
dc.contributor.authorOjamaa, Kaie-
dc.contributor.authorAl-Abed, Yousef-
dc.contributor.authorFaltys, Michael-
dc.contributor.authorPavlov, Valentin A.-
dc.contributor.authorAndersson, Ulf-
dc.contributor.authorChavan, Sangeeta S.-
dc.contributor.authorLevine, Yaakov A.-
dc.contributor.authorMak, Tak W.-
dc.contributor.authorTracey, Kevin J.-
dc.contributor.authorOlofsson, Peder S.-
dc.date.accessioned2020-11-17T14:55:45Z-
dc.date.available2020-11-17T14:55:45Z-
dc.date.issued2018-
dc.identifier.citationFrontiers in Immunology, 2018, v. 9, article no. 2648-
dc.identifier.urihttp://hdl.handle.net/10722/292093-
dc.description.abstractMacrophage 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.-
dc.languageeng-
dc.relation.ispartofFrontiers in Immunology-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectAdenylyl cyclase 6-
dc.subjectAcetylcholine-
dc.subjectΑ7nAChR-
dc.subjectVagus nerve stimulation/VNS-
dc.subjectInflammatory reflex-
dc.subjectCholine acetyltransferase-
dc.subjectSustained TNF inhibition-
dc.titleAdenylyl cyclase 6 mediates inhibition of TNF in the inflammatory reflex-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.3389/fimmu.2018.02648-
dc.identifier.pmid30538698-
dc.identifier.pmcidPMC6277584-
dc.identifier.scopuseid_2-s2.0-85057328698-
dc.identifier.volume9-
dc.identifier.spagearticle no. 2648-
dc.identifier.epagearticle no. 2648-
dc.identifier.eissn1664-3224-
dc.identifier.isiWOS:000451446800001-
dc.identifier.issnl1664-3224-

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