Inflammatory and autoimmune disorders are personally and financially costly and are not very responsive to current therapies. Toward a long-term goal of successfully treating these disorders, this project seeks to identify roles in them played by nicotinic acetylcholine receptors (nAChR), specifically, those containing ?9 subunits (?9*-nAChR). Cholinergic signaling and interplay between the immune, autonomic and central nervous systems have been implicated in inflammatory and anti-inflammatory responses. We and others have shown that nicotine exposure protects against inflammation and immune attack in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). However, our understanding is deficient about what specific nAChR are involved in anti- or pro-inflammatory responses, in immunity/ autoimmunity, and in immunosuppressive effects of nicotine, and about the cellular origins of these nAChR. Our preliminary findings suggest that ?9*-nAChR are richly expressed in the immune system, because nAChR ?9 subunit message levels are higher there than in the nervous system, perhaps except for the cochlea. Moreover, whereas nicotine protects against induction of EAE in wild-type mice, it seems to have no effect in mice lacking nAChR ?9 subunit expression. However, the temporal pattern for development of EAE and its severity in ?9-/- mice are like those in nicotine-treated, wild-type animals. That is, genetic deletion of ?9*-nAChR or their pharmacological block (nicotine is an antagonist of ?9*-nAChR function, in contrast to its effects as an agonist at other nAChR subtypes) seem to be equally protective against EAE. This exploratory/developmental project will test the overarching hypothesis that immune cell ?9*-nAChR play pro-inflammatory roles and are engaged in autoimmune responses.
One aim i s to define nAChR ?9 subunit expression profiles, under control conditions and in the course of inflammatory responses, in purified and/or sorted populations of peripheral or central immune cells. Another aim is to employ constitutive and conditional nAChR ?9 subunit knock-out mice to define roles for ?9*-nAChR in immune and inflammatory responses in the EAE model and in nicotine sensitivity of those responses. We expect to obtain essential information about the immune system distribution of ?9*-nAChR and to elucidate roles that they play in inflammation and autoimmune responsiveness in the EAE model of MS. This will provide insight into what seems to be critical involvement of ?9*-nAChR in cholinergic/nicotinic anti- inflammatory and immunosuppressive effects. Foundations will be laid for further mechanistic studies concerning ?9*-nAChR and examining the therapeutic potential of ?9*-nAChR subtype-selective ligands.

Public Health Relevance

There are serious shortcomings in viable treatments for devastating inflammatory and autoimmune disorders, such as multiple sclerosis (MS). Recent, exciting discoveries implicate the natural chemical messenger, acetylcholine, in immune and inflammatory responses and reveal important interactions between the immune and nervous systems. Success in this project identifying ?9*-nicotinic acetylcholine receptors in pro-inflammatory and immune responses would establish bases for development of novel therapies targeting those entities or downstream modulators in treatment of MS and perhaps other neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS082902-01A1
Application #
8638316
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2013-09-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$224,303
Indirect Cost
$57,926
Name
St. Joseph's Hospital and Medical Center
Department
Type
DUNS #
131606022
City
Phoenix
State
AZ
Country
United States
Zip Code
85013
Zhang, Cun-Jin; Zhai, Hui; Yan, Yaping et al. (2014) Glatiramer acetate ameliorates experimental autoimmune neuritis. Immunol Cell Biol 92:164-9
Tang, Zhiwei; Gan, Yan; Liu, Qiang et al. (2014) CX3CR1 deficiency suppresses activation and neurotoxicity of microglia/macrophage in experimental ischemic stroke. J Neuroinflammation 11:26