Alpha7 cholinergic-agonist prevents systemic inflammation by Sepsis. (179.3)

Abstract

The alpha7 nicotinic acetylcholine receptors (α7nAChR) play a critical role in modulating systemic inflammation in sepsis (1). However, α7nAChR-agonists have failed to provide significant advantages in several pilot studies with septic patients. Since we recently reported that the vagus nerve prevents sepsis by activating regulatory lymphocytes (2), we reasoned that the massive apoptosis of lymphocytes during sepsis may prevent the therapeutic effects of the α7nAChR-agonists. Our results indicate that α7nAChR-agonists failed to prevent systemic inflammation in lymphocyte-deficient nude mice. The transfer of typical regulatory CD3+CD4+CD25+ suppressor/regulatory lymphocytes failed to reestablish the benefits of α7nAChR-agonists. But, the transfer of CD3+CD4+CD25- modulatory lymphocytes reestablished the anti-inflammatory potential of the α7nAChR-agonists. Likewise, α7nAChR-agonist prevented systemic inflammation in polymicrobial sepsis when administered before sepsis. The anti-inflammatory potential and benefits of the α7nAChR-agonists vanishes as the treatment is delayed after the onset of the infection. However, the adoptive transfer of CD3+CD4+CD25- modulatory lymphocytes reestablished the anti-inflammatory potential of the α7nAChR-agonists, even if the treatment is started long after the infection. These results suggest that a new set of CD25- modulatory lymphocytes can provide clinical advantages for the treatment of infections and inflammatory disorders.