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

Eran Nizri,^* Michal Irony-Tur-Sinai,^* Omer Lory,^* Avi Orr-Urtreger, Ehud Lavi, and Talma Brenner^1*

^*Laboratory of Neuroimmunology, Department of Neurology and the Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; The Genetic Institute, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; and Department of Pathology and Laboratory of Medicine, Weill Medical College, Cornell University and New York Presbyterian Hospital, New York, NY 10065

The 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 7 nAChR activation by nicotine. Our results indicate that the 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- and IFN-) 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, 7^–/–-derived T cells were unaffected by nicotine. Furthermore, nicotine reduced NF-B-mediated transcription as measured by IL-2 and IB transcription. In vivo, administration of nicotine (2 mg/kg s.c.) suppressed the severity of CD4⁺ T cell-mediated disease experimental autoimmune encephalomyelitis. 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 7 nAChR in immune modulation and suggest that 7 nAChR agonists may be effective in the treatment of inflammatory disorders.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Talma Brenner, Laboratory of Neuroimmunology, Department of Neurology, Hadassah-Hebrew University Medical Center, P.O. Box 12000, Jerusalem, Israel. E-mail address: brenner{at}cc.huji.ac.il

² Abbreviations used in this paper: nAChR, nicotinic acetylcholine receptor; ACh, acetylcholine; -btx, -bungarotoxin; AS, antisense; EAE, experimental autoimmune encephalomyelitis; HPRT, hypoxanthine phosphoribosyltransferase; KO, knockout; LNC, lymph node cell; MOG, myelin oligodendrocyte glycoprotein; SI, stimulation index; TF, transcription factor; UC, ulcerative colitis; WT, wild type.