Activation of the Cholinergic Anti-Inflammatory System by Nicotine Attenuates Neuroinflammation via Suppression of Th1 and Th17 Responses

The alpha 7 nicotinic acetylcholine receptor (nAChR) was recently described as an anti-inflammatory target in both macrophages and T cells. Its expression by immune cells may explain the epidemiological data claiming a negative link between cigarette smoking and several inflammatory diseases. In this study, we determined the immunological effects of alpha 7 nAChR activation by nicotine. Our results indicate that the alpha 7 nAChR is expressed on the surface of CD4(+) T cells and that this expression is up-regulated upon immune activation. Nicotine reduced T cell proliferation in response to an encephalitogenic Ag, as well as the production of Th1 (TNF-alpha and IFN-gamma) and Th17 cytokines (IL-17, IL-17F, IL-21, and IL-22). IL-4 production was increased in the same setting. Attenuation of the Th1 and Th17 lineages was accompanied by reduced T-bet (50%) and increased GATA-3 (350%) expression. Overall, nicotine induced a shift to the Th2 lineage. However, alpha 7(-/-)-derived T cells were unaffected by nicotine. Furthermore, nicotine reduced NF-kappa B-mediated transcription as measured by IL-2 and I kappa B transcription. In vivo, administration of nicotine (2 mg/kg s.c.) suppressed the severity of CD4(+) T cell-mediated disease experimental autoimmune encephalomyelitis. alpha 7(-/-) mice were refractory to nicotine treatment, although disease severity in those animals was reduced, due to impairment in Ag presentation. Accordingly, CD4(+) and CD11b(+) cells infiltration into the CNS, demyelination, and axonal loss were reduced. Our data implicate a role for the alpha 7 nAChR in immune modulation and suggest that alpha 7 nAChR agonists may be effective in the treatment of inflammatory disorders. The Journal of Immunology, 2009, 183: 6681-6688.