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

Abstract

The α7 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 α7 nAChR activation by nicotine. Our results indicate that the α7 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-α and IFN-γ) 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, α7−/−-derived T cells were unaffected by nicotine. Furthermore, nicotine reduced NF-κB-mediated transcription as measured by IL-2 and IκB transcription. In vivo, administration of nicotine (2 mg/kg s.c.) suppressed the severity of CD4+ T cell-mediated disease experimental autoimmune encephalomyelitis. α7−/− 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 α7 nAChR in immune modulation and suggest that α7 nAChR agonists may be effective in the treatment of inflammatory disorders.

Plasticity of the murine spleen T-cell cholinergic receptors and their role in in vitro differentiation of naïve CD4 T cells toward the Th1, Th2 and Th17 lineages

“…30 The factors that can affect both the repertoire and the ligandbinding affinities of cholinergic receptors include the dose and duration of exposure to an agonist, antigen stimulation, cytokine milieu and a large variety of other non-immunological and immunological stimulations. [2][3][4]10,22,[31][32][33][34][35][36][37][38] This helps in explaining the discrepancy of our in vitro findings with the previous report that nicotine treatment of mice with experimental autoimmune encephalomyelitis fosters a shift from Th1 toward Th2 or Th3 responses. 38 In that study, however, the reduction in secreted IFN-g was most marked in CD8 compared with CD4 cells.…”

“…The signaling downstream of a7 nAChR on T cells controls inflammatory responses and a7 À/À -derived T cells were unaffected by nicotine. 22 We have previously demonstrated that upon immunization with ovalbumin, the a7 nAChR knockout mice develop increased serum level of antigen-specific IgG 1 . 23 In marked contrast, immunized M 1 /M 5 mAChR knockout mice show diminished antigen-specific IgG 1 production.…”

“…dendritic cells 25 and suppresses Th17 response. 22 Of note, exposure of human lamina propria T cells to nicotine upregulates expression of the Th1-specific transcription factor T-bet without affecting the Th2-specific transcription factor GATA-3, thus skewing the immune response toward Th1-dominant pattern. 46 Taken together, these findings provide a solid evidence that signaling along the nicotinic arm of the ACh regulatory axis of murine and human T cells augments Th1 polarization, whereas the muscarinic arm facilitates Th2 and Th17 differentiation.…”

The cholinergic anti-inflammatory pathway ameliorates acute viral myocarditis in mice by regulating CD4+ T cell differentiation

“…Wu et al found that the CAP reduced the percentage of Th17 cells, increased the percentage of Th2 cells and attenuated the inflammatory response of arthritis in mice [16]. Nizri et al also demonstrated that nicotine treatment inhibited the response of Th1 and Th17 cells and attenuated neuroinflammation in autoimmunity encephalomyelitis [17]. Nicotine treatment could ameliorate inflammatory bowel disease severity through increasing the proportion of Treg cells and decreasing the proportion of Th17 cells [11].…”

The Immune System’s Moderating Response to Inflammation Relieves Autistic Behavior: Response to Peter Good

“…An outpouring of cytokines from activated microglia, the CNS counterparts of macrophages, involves the excessive release of glutamate, the preponderant excitatory neurotransmitter, increasing the brain activation toward hyperarousal. By subduing neuroinflammation (Nizri et al 2009), the CAIS would downregulate arousal and enable adaptive behavior to emerge.…”