Abstract 15836: The Role of the Cholinergic Antiinflammatory Pathway in Murine Autoimmune Myocarditis
Objectives: Recent studies revealed an immuno-modulatory property of the vagus nerve referred to as the cholinergic anti-inflammatory pathway. Chemical stimulation of the efferent arm of the vagus nerve through the activation of the nicotinic acetylcholine receptor subtype 7alpha (alpha7nAChR) has been shown to be protective in several models of inflammatory diseases. In the present study, we investigated the potentially protective effect of vagus nerve stimulation on myocarditis.
Methods: A/J mice were immunized with cardiac troponin I (cTnI) to induce autoimmune myocarditis. Mice were then exposed to drinking water containing nicotine (alpha7nAChR agonist) in different concentrations and at different time periods (3 days 12,5 mg/l; 3 days 125 mg/l; 21 days 12,5 mg/l; 21 days 125 mg/l). Additionally, we tested the potential anti-inflammatory effect of the acetylcholineesterase inhibitor, neostigmine.
Results: cTnI immunized mice with no pharmacological treatment showed an extensive myocardial inflammation (Hematoxylin & eosin and Masson's trichrome staining, p=0,04) and significantly elevated levels of pro-inflammatory cytokines (IL-6, p=0,006 and TNF-α, p=0,001). Furthermore, elevated levels of mRNA transcripts of pro-inflammatory chemokines (MCP-1, RANTES) and chemokine receptors (CCR1, CCR2, CCR5) were found. Both chronic and short term oral nicotine application significantly reduced inflammation within the myocardium, decreased the production of IL-6 and TNF-α and downregulated the expression of MCP1, RANTES, CCR1, CCR2 and CCR5. Finally, we found that higher oral doses of nicotine (125 mg/l) reduced pSTAT3 protein levels in immunized mice, suggesting that signal transduction in this anti-inflammatory pathway are mediated through the JAK2/STAT3 pathway. Interestingly, neostigmine treatment was not protective and abrogated the cardio-protective effect of nicotine treatment.
Conclusions: Taken together, our study revealed for the first time that activation of the cholinergic anti-inflammatory pathway via nicotine protects from myocarditis, which may open new possibilities in the therapeutic management of autoimmune myocarditis.
- © 2010 by American Heart Association, Inc.