Differential modulation of EAE by alpha 9(star)- and beta 2(star)-nicotinic acetylcholine receptors

作者：Simard Alain R^*; Gan Yan; St Pierre Stephanie; Kousari Ariana; Patel Varun; Whiteaker Paul; Morley Barbara J; Lukas Ronald J; Shi Fu Dong

来源：Immunology and Cell Biology, 2013, 91(3): 195-200.

DOI：10.1038/icb.2013.1

• autoimmunity
• cholinergic anti-inflammatory pathway
• experimental autoimmune encephalomyelitis
• inflammation
• multiple sclerosis
• nicotinic acetylcholine receptors

Nicotine is a potent inhibitor of the immune response and is protective against experimental autoimmune encephalomyelitis (EAE). Initial studies suggested that the cholinergic system modulates inflammation via the alpha 7-nicotinic acetylcholine receptor (nAChR) subtype. We recently have shown that effector T cells and myeloid cells constitutively express mRNAs encoding nAChR alpha 9 and beta 2 subunits and found evidence for immune system roles for non-alpha 7-nAChRs. In the present study, we assessed the effects of nAChR alpha 9 or beta 2 subunit gene deletion on EAE onset and severity, with or without nicotine treatment. We report again that disease onset is delayed and severity is attenuated in nicotine-treated, wild-type mice, an effect that also is observed in a9 subunit knock-out (KO) mice irrespective of nicotine treatment. On the other hand, beta 2 KO mice fail to recover from peak measures of disease severity regardless of nicotine treatment, despite retaining sensitivity to nicotine's attenuation of disease severity. Prior to disease onset, we found significantly less reactive oxygen species production in the central nervous system (CNS) of beta 2 KO mice, elevated proportions of CNS myeloid cells but decreased ratios of CNS macrophages/microglia in alpha 9 or beta 2 KO mice, and some changes in iNOS, INF-alpha and IL-1 beta mRNA levels in alpha 9 KO and/or beta 2 KO mice. Our data thus suggest that beta 2(star)- and alpha 9(star)-nAChRs, in addition to alpha 7-nAChRs, have different roles in endogenous and nicotine-dependent modulation of immune functions and could be exploited as therapeutic targets to modulate inflammation and autoimmunity. Immunology and Cell Biology (2013) 91, 195-200; doi:10.1038/icb.2013.1; published online 12 February 2013

• 出版日期2013-3