Circulating extracellular choline acetyltransferase regulates inflammation.
acetylcholine
anti-inflammatory
inflammatory bowel disease
inflammatory reflex
sepsis
Journal
Journal of internal medicine
ISSN: 1365-2796
Titre abrégé: J Intern Med
Pays: England
ID NLM: 8904841
Informations de publication
Date de publication:
27 Nov 2023
27 Nov 2023
Historique:
medline:
28
11
2023
pubmed:
28
11
2023
entrez:
27
11
2023
Statut:
aheadofprint
Résumé
Choline acetyltransferase (ChAT) is required for the biosynthesis of acetylcholine, the molecular mediator that inhibits cytokine production in the cholinergic anti-inflammatory pathway of the vagus nerve inflammatory reflex. Abundant work has established the biology of cytoplasmic ChAT in neurons, but much less is known about the potential presence and function of ChAT in the extracellular milieu. We evaluated the hypothesis that extracellular ChAT activity responds to inflammation and serves to inhibit cytokine release and attenuate inflammation. After developing novel methods for quantification of ChAT activity in plasma, we determined whether ChAT activity changes in response to inflammatory challenges. Active ChAT circulates within the plasma compartment of mice and responds to immunological perturbations. Following the administration of bacterial endotoxin, plasma ChAT activity increases for 12-48 h, a time period that coincides with declining tumor necrosis factor (TNF) levels. Further, a direct activation of the cholinergic anti-inflammatory pathway by vagus nerve stimulation significantly increases plasma ChAT activity, whereas the administration of bioactive recombinant ChAT (r-ChAT) inhibits endotoxin-stimulated TNF production and anti-ChAT antibodies exacerbate endotoxin-induced TNF levels, results of which suggest that ChAT activity regulates endogenous TNF production. Administration of r-ChAT significantly attenuates pro-inflammatory cytokine production and disease activity in the dextran sodium sulfate preclinical model of inflammatory bowel disease. Finally, plasma ChAT levels are also elevated in humans with sepsis, with the highest levels observed in a patient who succumbed to infection. As a group, these results support further investigation of ChAT as a counter-regulator of inflammation and potential therapeutic agent.
Sections du résumé
BACKGROUND
BACKGROUND
Choline acetyltransferase (ChAT) is required for the biosynthesis of acetylcholine, the molecular mediator that inhibits cytokine production in the cholinergic anti-inflammatory pathway of the vagus nerve inflammatory reflex. Abundant work has established the biology of cytoplasmic ChAT in neurons, but much less is known about the potential presence and function of ChAT in the extracellular milieu.
OBJECTIVES
OBJECTIVE
We evaluated the hypothesis that extracellular ChAT activity responds to inflammation and serves to inhibit cytokine release and attenuate inflammation.
METHODS
METHODS
After developing novel methods for quantification of ChAT activity in plasma, we determined whether ChAT activity changes in response to inflammatory challenges.
RESULTS
RESULTS
Active ChAT circulates within the plasma compartment of mice and responds to immunological perturbations. Following the administration of bacterial endotoxin, plasma ChAT activity increases for 12-48 h, a time period that coincides with declining tumor necrosis factor (TNF) levels. Further, a direct activation of the cholinergic anti-inflammatory pathway by vagus nerve stimulation significantly increases plasma ChAT activity, whereas the administration of bioactive recombinant ChAT (r-ChAT) inhibits endotoxin-stimulated TNF production and anti-ChAT antibodies exacerbate endotoxin-induced TNF levels, results of which suggest that ChAT activity regulates endogenous TNF production. Administration of r-ChAT significantly attenuates pro-inflammatory cytokine production and disease activity in the dextran sodium sulfate preclinical model of inflammatory bowel disease. Finally, plasma ChAT levels are also elevated in humans with sepsis, with the highest levels observed in a patient who succumbed to infection.
CONCLUSION
CONCLUSIONS
As a group, these results support further investigation of ChAT as a counter-regulator of inflammation and potential therapeutic agent.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
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