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Histone Deacetylase Isoforms Differentially Modulate Inflammatory and Autoantibody Responses in a Mouse Model of Myasthenia Gravis

Myasthenia gravis (MG) is an autoimmune disease characterized by chronic muscle fatigue and weakness caused by autoantibodies and complement-mediated damage at neuromuscular junctions. Histone deacetylases (HDACs) are crucial epigenetic regulators of proinflammatory gene expression; however, it is u...

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Autores principales: Bahauddin, Afrin, Ivannikov, Maxim, Wang, Zhongying, Jamaluddin, Mohammad, Curtis, Kyra, Ibtehaj, Naazneen, Yeager, Linsey, Soong, Lynn, Fang, Xiang, Huda, Ruksana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8866970/
https://www.ncbi.nlm.nih.gov/pubmed/35222229
http://dx.doi.org/10.3389/fneur.2021.804113
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author Bahauddin, Afrin
Ivannikov, Maxim
Wang, Zhongying
Jamaluddin, Mohammad
Curtis, Kyra
Ibtehaj, Naazneen
Yeager, Linsey
Soong, Lynn
Fang, Xiang
Huda, Ruksana
author_facet Bahauddin, Afrin
Ivannikov, Maxim
Wang, Zhongying
Jamaluddin, Mohammad
Curtis, Kyra
Ibtehaj, Naazneen
Yeager, Linsey
Soong, Lynn
Fang, Xiang
Huda, Ruksana
author_sort Bahauddin, Afrin
collection PubMed
description Myasthenia gravis (MG) is an autoimmune disease characterized by chronic muscle fatigue and weakness caused by autoantibodies and complement-mediated damage at neuromuscular junctions. Histone deacetylases (HDACs) are crucial epigenetic regulators of proinflammatory gene expression; however, it is unclear whether HDACs modulate chronic inflammation or autoantibody production associated with MG pathogenesis. We examined expression profiles and serum levels of key inflammatory cytokines (IL-6 and IL-21) and acetylcholine receptor (AChR)-specific autoantibodies following pharmacological inhibition of key HDAC isoforms in a mouse model of MG. We found that HDAC inhibition significantly reduced the production of IL-6, but not IL-21, in AChR-stimulated PBMCs and splenocytes (n = 5 per group). Trichostatin (pan-HDAC inhibitor) treatment of MG-PBMCs (n = 2) also exhibited reduced production of induced IL-6. Although HDAC1 inhibition lowered IL-6 levels the most, HDAC2 inhibition depleted intracellular IL-6 and markedly reduced serum anti-AChR IgG2b in EAMG mice. The transcriptomic profiling and pathway mapping also revealed that autoimmunity-linked, major cell signaling pathways were differentially altered by HDAC1/2 inhibition. HDAC inhibition-mediated reduction in IL-6 and autoantibody levels also correlated with milder disease and preservation of muscle AChR in the treated mice. Overall, our findings revealed isoform-specific functional variance of HDACs in reducing inflammation and identified HDAC-regulated many genes underlying specific inflammatory and autoantibody pathways in EAMG. Thus, the study provides a rationale for further research to evaluate the HDACs or their gene targets as a potential adjunct treatment for MG.
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spelling pubmed-88669702022-02-25 Histone Deacetylase Isoforms Differentially Modulate Inflammatory and Autoantibody Responses in a Mouse Model of Myasthenia Gravis Bahauddin, Afrin Ivannikov, Maxim Wang, Zhongying Jamaluddin, Mohammad Curtis, Kyra Ibtehaj, Naazneen Yeager, Linsey Soong, Lynn Fang, Xiang Huda, Ruksana Front Neurol Neurology Myasthenia gravis (MG) is an autoimmune disease characterized by chronic muscle fatigue and weakness caused by autoantibodies and complement-mediated damage at neuromuscular junctions. Histone deacetylases (HDACs) are crucial epigenetic regulators of proinflammatory gene expression; however, it is unclear whether HDACs modulate chronic inflammation or autoantibody production associated with MG pathogenesis. We examined expression profiles and serum levels of key inflammatory cytokines (IL-6 and IL-21) and acetylcholine receptor (AChR)-specific autoantibodies following pharmacological inhibition of key HDAC isoforms in a mouse model of MG. We found that HDAC inhibition significantly reduced the production of IL-6, but not IL-21, in AChR-stimulated PBMCs and splenocytes (n = 5 per group). Trichostatin (pan-HDAC inhibitor) treatment of MG-PBMCs (n = 2) also exhibited reduced production of induced IL-6. Although HDAC1 inhibition lowered IL-6 levels the most, HDAC2 inhibition depleted intracellular IL-6 and markedly reduced serum anti-AChR IgG2b in EAMG mice. The transcriptomic profiling and pathway mapping also revealed that autoimmunity-linked, major cell signaling pathways were differentially altered by HDAC1/2 inhibition. HDAC inhibition-mediated reduction in IL-6 and autoantibody levels also correlated with milder disease and preservation of muscle AChR in the treated mice. Overall, our findings revealed isoform-specific functional variance of HDACs in reducing inflammation and identified HDAC-regulated many genes underlying specific inflammatory and autoantibody pathways in EAMG. Thus, the study provides a rationale for further research to evaluate the HDACs or their gene targets as a potential adjunct treatment for MG. Frontiers Media S.A. 2022-02-10 /pmc/articles/PMC8866970/ /pubmed/35222229 http://dx.doi.org/10.3389/fneur.2021.804113 Text en Copyright © 2022 Bahauddin, Ivannikov, Wang, Jamaluddin, Curtis, Ibtehaj, Yeager, Soong, Fang and Huda. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neurology
Bahauddin, Afrin
Ivannikov, Maxim
Wang, Zhongying
Jamaluddin, Mohammad
Curtis, Kyra
Ibtehaj, Naazneen
Yeager, Linsey
Soong, Lynn
Fang, Xiang
Huda, Ruksana
Histone Deacetylase Isoforms Differentially Modulate Inflammatory and Autoantibody Responses in a Mouse Model of Myasthenia Gravis
title Histone Deacetylase Isoforms Differentially Modulate Inflammatory and Autoantibody Responses in a Mouse Model of Myasthenia Gravis
title_full Histone Deacetylase Isoforms Differentially Modulate Inflammatory and Autoantibody Responses in a Mouse Model of Myasthenia Gravis
title_fullStr Histone Deacetylase Isoforms Differentially Modulate Inflammatory and Autoantibody Responses in a Mouse Model of Myasthenia Gravis
title_full_unstemmed Histone Deacetylase Isoforms Differentially Modulate Inflammatory and Autoantibody Responses in a Mouse Model of Myasthenia Gravis
title_short Histone Deacetylase Isoforms Differentially Modulate Inflammatory and Autoantibody Responses in a Mouse Model of Myasthenia Gravis
title_sort histone deacetylase isoforms differentially modulate inflammatory and autoantibody responses in a mouse model of myasthenia gravis
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8866970/
https://www.ncbi.nlm.nih.gov/pubmed/35222229
http://dx.doi.org/10.3389/fneur.2021.804113
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