title: Differential modulation of EAE by α9*- and β2*-nicotinic acetylcholine receptors.
abstract: 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 α7-nicotinic acetylcholine receptor (nAChR) subtype. We recently have shown that effector T cells and myeloid cells constitutively express mRNAs encoding nAChR α9 and β2 subunits and found evidence for immune system roles for non-α7-nAChRs. In the present study, we assessed the effects of nAChR α9 or β2 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 α9 subunit knock-out (KO) mice irrespective of nicotine treatment. On the other hand, β2 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 β2 KO mice, elevated proportions of CNS myeloid cells but decreased ratios of CNS macrophages/microglia in α9 or β2 KO mice, and some changes in iNOS, TNF-α and IL-1β mRNA levels in α9 KO and/or β2 KO mice. Our data thus suggest that β2*- and α9*-nAChRs, in addition to α7-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.
authors: Département de Chimie et Biochimie, Université de Moncton, Moncton, New Brunswick, Canada. alain.simard@umoncton.ca
authors: Alain R
authors: AR
authors: Simard
authors: Yan
authors: Y
authors: Gan
authors: Stéphanie
authors: S
authors: St-Pierre
authors: Ariana
authors: A
authors: Kousari
authors: Varun
authors: V
authors: Patel
authors: Paul
authors: P
authors: Whiteaker
authors: Barbara J
authors: BJ
authors: Morley
authors: Ronald J
authors: RJ
authors: Lukas
authors: Fu-Dong
authors: FD
authors: Shi
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D017353:Gene Deletion; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology* / Q000473:pathology; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology; D011978:Receptors, Nicotinic / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D053583:Interleukin-1beta; D009538:Nicotine; D018722:Nicotinic Agonists; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; C402445:Chrna9 protein, mouse; C496317:Nos2 protein, mouse
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