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Attenuation of CNS inflammatory responses by nicotine involves ?7 and non-?7 nicotinic receptors.

ABSTRACT: A considerable number of in vivo studies have demonstrated that the cholinergic system can dampen the peripheral immune response, and it is thought that the ?7-nicotinic acetylcholine receptor (nAChR) subtype is a key mediator of this process. The goal of the present study was to determine if nicotine modulates immunological mechanisms known to be involved in the development of experimental autoimmune encephalomyelitis (EAE), a mouse model for CNS autoimmune disease, via ?7-nAChRs. Here we show that nicotine exposure attenuates EAE severity and that this effect is largely abolished in nAChR ?7 subunit knock-out mice. However, nicotine exposure partially retains the ability to reduce lymphocyte infiltration into the CNS, inhibit auto-reactive T cell proliferation and helper T cell cytokine production, down-regulate co-stimulatory protein expression on myeloid cells, and increase the differentiation and recruitment of regulatory T cells, even in the absence of ?7-nAChRs. Diverse effects of nicotine on effector and regulatory T cells, as well as antigen-presenting cells, may be linked to differential expression patterns of nAChR subunits across these cell types. Taken together, our data show that although ?7-nAChRs indeed seem to play an important role in nicotine-conferred reduction of the CNS inflammatory response and protection against EAE, other nAChR subtypes also are involved in the anti-inflammatory properties of the cholinergic system.

SUBMITTER: Hao J

PROVIDER: S-EPMC3019302 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Attenuation of CNS inflammatory responses by nicotine involves α7 and non-α7 nicotinic receptors.

Hao Junwei J Simard Alain R AR Turner Gregory H GH Wu Jie J Whiteaker Paul P Lukas Ronald J RJ Shi Fu-Dong FD

Experimental neurology 20101013 1

A considerable number of in vivo studies have demonstrated that the cholinergic system can dampen the peripheral immune response, and it is thought that the α7-nicotinic acetylcholine receptor (nAChR) subtype is a key mediator of this process. The goal of the present study was to determine if nicotine modulates immunological mechanisms known to be involved in the development of experimental autoimmune encephalomyelitis (EAE), a mouse model for CNS autoimmune disease, via α7-nAChRs. Here we show ...[more]

PMID: 20932827

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Project description:BackgroundEvidence suggests that the activation of α7 nicotinic acetylcholine receptor (α7nAChR) can greatly decrease the neuroinflammation response. Neuroinflammation plays a pivotal role in the pathogenesis of chronic migraine (CM). Clinical observations also show that nicotine gum induces analgesic effects in migraine patients. However, whether α7nAChR is involved in CM is unclear.ObjectiveTo investigate the role of α7nAChR in CM and provide a new therapeutic target for CM.Materials and methodsThirty-six male Sprague-Dawley rats were distributed randomly into control, CM, PNU-282987, and α-bungarotoxin groups (n=9 rats in each group). The CM model was established by the recurrent daily administration of inflammatory soup on the dura over the course of 1 week. The hind paw threshold and facial allodynia were assessed by the von Frey test. The expression levels of α7nAChR, tumor necrosis factor-alpha, and interleukin-1 beta were analyzed by Western blot and real-time fluorescence quantitative polymerase chain reaction. The location of α7nAChR in the hippocampus was quantified by immunofluorescence, as well as the microglial and astrocyte alterations. Changes in the calcitonin gene-related peptide and the phosphorylated JNK protein among different groups were measured by Western blot.ResultsWe found that the expression of α7nAChR was reduced after repeated inflammatory soup administration. The increased expression of tumor necrosis factor-alpha, interleukin-1 beta, and calcitonin gene-related peptide in CM group were significantly decreased by PNU-282987 and aggravated by α-bungarotoxin. Moreover, PNU-282987 decreased the numbers of astrocytes and microglia compared with the numbers in the CM group in both hippocampal CA1 and CA3 regions. In contrast, α-bungarotoxin activated the astrocytes and microglia, but the differences with respect to the CM group were not significant. Activated c-Jun N-terminal kinase signaling was observed in CM rats and was also blocked by PNU-282987.ConclusionThe activation of α7nAChR increased the mechanical threshold and alleviated pain in the CM rat model. α7nAChR activation also decreased the upregulation of astrocytes and microglia through the p-c-Jun N-terminal kinase-mitogen-activated protein kinase signaling pathway.

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Attenuation of CNS inflammatory responses by nicotine involves ?7 and non-?7 nicotinic receptors.

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Attenuation of CNS inflammatory responses by nicotine involves α7 and non-α7 nicotinic receptors.

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