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Attenuation in Nicotinic Acetylcholine Receptor α9 and α10 Subunit Double Knock-Out Mice of Experimental Autoimmune Encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is attenuated in nicotinic acetylcholine receptor (nAChR) α9 subunit knock-out (α9 KO) mice. However, protection is incomplete, raising questions about roles for related, nAChR α10 subunits in ionotropic or recently-revealed metabotropic contributions...

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Autores principales: Liu, Qiang, Li, Minshu, Whiteaker, Paul, Shi, Fu-Dong, Morley, Barbara J., Lukas, Ronald J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995583/
https://www.ncbi.nlm.nih.gov/pubmed/31817275
http://dx.doi.org/10.3390/biom9120827
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author Liu, Qiang
Li, Minshu
Whiteaker, Paul
Shi, Fu-Dong
Morley, Barbara J.
Lukas, Ronald J.
author_facet Liu, Qiang
Li, Minshu
Whiteaker, Paul
Shi, Fu-Dong
Morley, Barbara J.
Lukas, Ronald J.
author_sort Liu, Qiang
collection PubMed
description Experimental autoimmune encephalomyelitis (EAE) is attenuated in nicotinic acetylcholine receptor (nAChR) α9 subunit knock-out (α9 KO) mice. However, protection is incomplete, raising questions about roles for related, nAChR α10 subunits in ionotropic or recently-revealed metabotropic contributions to effects. Here, we demonstrate reduced EAE severity and delayed onset of disease signs in nAChR α9/α10 subunit double knock-out (DKO) animals relative to effects in wild-type (WT) control mice. These effects are indistinguishable from contemporaneously-observed effects in nicotine-treated WT or in α9 KO mice. Immune cell infiltration into the spinal cord and brain, reactive oxygen species levels in vivo, and demyelination, mostly in the spinal cord, are reduced in DKO mice. Disease severity is not altered relative to WT controls in mice harboring a gain-of-function mutation in α9 subunits. These findings minimize the likelihood that additional deletion of nAChR α10 subunits impacts disease differently than α9 KO alone, whether through ionotropic, metabotropic, or alternative mechanisms. Moreover, our results provide further evidence of disease-exacerbating roles for nAChR containing α9 subunits (α9*-nAChR) in EAE inflammatory and autoimmune responses. This supports our hypothesis that α9*-nAChR or their downstream mediators are attractive targets for attenuation of inflammation and autoimmunity.
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spelling pubmed-69955832020-02-13 Attenuation in Nicotinic Acetylcholine Receptor α9 and α10 Subunit Double Knock-Out Mice of Experimental Autoimmune Encephalomyelitis Liu, Qiang Li, Minshu Whiteaker, Paul Shi, Fu-Dong Morley, Barbara J. Lukas, Ronald J. Biomolecules Article Experimental autoimmune encephalomyelitis (EAE) is attenuated in nicotinic acetylcholine receptor (nAChR) α9 subunit knock-out (α9 KO) mice. However, protection is incomplete, raising questions about roles for related, nAChR α10 subunits in ionotropic or recently-revealed metabotropic contributions to effects. Here, we demonstrate reduced EAE severity and delayed onset of disease signs in nAChR α9/α10 subunit double knock-out (DKO) animals relative to effects in wild-type (WT) control mice. These effects are indistinguishable from contemporaneously-observed effects in nicotine-treated WT or in α9 KO mice. Immune cell infiltration into the spinal cord and brain, reactive oxygen species levels in vivo, and demyelination, mostly in the spinal cord, are reduced in DKO mice. Disease severity is not altered relative to WT controls in mice harboring a gain-of-function mutation in α9 subunits. These findings minimize the likelihood that additional deletion of nAChR α10 subunits impacts disease differently than α9 KO alone, whether through ionotropic, metabotropic, or alternative mechanisms. Moreover, our results provide further evidence of disease-exacerbating roles for nAChR containing α9 subunits (α9*-nAChR) in EAE inflammatory and autoimmune responses. This supports our hypothesis that α9*-nAChR or their downstream mediators are attractive targets for attenuation of inflammation and autoimmunity. MDPI 2019-12-04 /pmc/articles/PMC6995583/ /pubmed/31817275 http://dx.doi.org/10.3390/biom9120827 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Liu, Qiang
Li, Minshu
Whiteaker, Paul
Shi, Fu-Dong
Morley, Barbara J.
Lukas, Ronald J.
Attenuation in Nicotinic Acetylcholine Receptor α9 and α10 Subunit Double Knock-Out Mice of Experimental Autoimmune Encephalomyelitis
title Attenuation in Nicotinic Acetylcholine Receptor α9 and α10 Subunit Double Knock-Out Mice of Experimental Autoimmune Encephalomyelitis
title_full Attenuation in Nicotinic Acetylcholine Receptor α9 and α10 Subunit Double Knock-Out Mice of Experimental Autoimmune Encephalomyelitis
title_fullStr Attenuation in Nicotinic Acetylcholine Receptor α9 and α10 Subunit Double Knock-Out Mice of Experimental Autoimmune Encephalomyelitis
title_full_unstemmed Attenuation in Nicotinic Acetylcholine Receptor α9 and α10 Subunit Double Knock-Out Mice of Experimental Autoimmune Encephalomyelitis
title_short Attenuation in Nicotinic Acetylcholine Receptor α9 and α10 Subunit Double Knock-Out Mice of Experimental Autoimmune Encephalomyelitis
title_sort attenuation in nicotinic acetylcholine receptor α9 and α10 subunit double knock-out mice of experimental autoimmune encephalomyelitis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995583/
https://www.ncbi.nlm.nih.gov/pubmed/31817275
http://dx.doi.org/10.3390/biom9120827
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