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Regulation of B cell functions by S-nitrosoglutathione in the EAE model

B cells play both protective and pathogenic roles in T cell-mediated autoimmune diseases by releasing regulatory vs. pathogenic cytokines. B cell-depleting therapy has been attempted in various autoimmune diseases but its efficacy varies and can even worsen symptoms due to depletion of B cells relea...

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Autores principales: Kim, Judong, Islam, S.M. Touhidul, Qiao, Fei, Singh, Avtar K., Khan, Mushfiquddin, Won, Jeseong, Singh, Inderjit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246645/
https://www.ncbi.nlm.nih.gov/pubmed/34175668
http://dx.doi.org/10.1016/j.redox.2021.102053
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author Kim, Judong
Islam, S.M. Touhidul
Qiao, Fei
Singh, Avtar K.
Khan, Mushfiquddin
Won, Jeseong
Singh, Inderjit
author_facet Kim, Judong
Islam, S.M. Touhidul
Qiao, Fei
Singh, Avtar K.
Khan, Mushfiquddin
Won, Jeseong
Singh, Inderjit
author_sort Kim, Judong
collection PubMed
description B cells play both protective and pathogenic roles in T cell-mediated autoimmune diseases by releasing regulatory vs. pathogenic cytokines. B cell-depleting therapy has been attempted in various autoimmune diseases but its efficacy varies and can even worsen symptoms due to depletion of B cells releasing regulatory cytokines along with B cells releasing pathogenic cytokines. Here, we report that S-nitrosoglutathione (GSNO) and GSNO-reductase (GSNOR) inhibitor N6022 drive upregulation of regulatory cytokine (IL-10) and downregulation of pathogenic effector cytokine (IL-6) in B cells and protected against the neuroinflammatory disease of experimental autoimmune encephalomyelitis (EAE). In human and mouse B cells, the GSNO/N6022-mediated regulation of IL-10 vs. IL-6 was not limited to regulatory B cells but also to a broad range of B cell subsets and antibody-secreting cells. Adoptive transfer of B cells from N6022 treated EAE mice or EAE mice deficient in the GSNOR gene also regulated T cell balance (Treg > Th17) and reduced clinical disease in the recipient EAE mice. The data presented here provide evidence of the role of GSNO in shifting B cell immune balance (IL-10 > IL-6) and the preclinical relevance of N6022, a first-in-class drug targeting GSNOR with proven human safety, as therapeutics for autoimmune disorders including multiple sclerosis.
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spelling pubmed-82466452021-07-06 Regulation of B cell functions by S-nitrosoglutathione in the EAE model Kim, Judong Islam, S.M. Touhidul Qiao, Fei Singh, Avtar K. Khan, Mushfiquddin Won, Jeseong Singh, Inderjit Redox Biol Research Paper B cells play both protective and pathogenic roles in T cell-mediated autoimmune diseases by releasing regulatory vs. pathogenic cytokines. B cell-depleting therapy has been attempted in various autoimmune diseases but its efficacy varies and can even worsen symptoms due to depletion of B cells releasing regulatory cytokines along with B cells releasing pathogenic cytokines. Here, we report that S-nitrosoglutathione (GSNO) and GSNO-reductase (GSNOR) inhibitor N6022 drive upregulation of regulatory cytokine (IL-10) and downregulation of pathogenic effector cytokine (IL-6) in B cells and protected against the neuroinflammatory disease of experimental autoimmune encephalomyelitis (EAE). In human and mouse B cells, the GSNO/N6022-mediated regulation of IL-10 vs. IL-6 was not limited to regulatory B cells but also to a broad range of B cell subsets and antibody-secreting cells. Adoptive transfer of B cells from N6022 treated EAE mice or EAE mice deficient in the GSNOR gene also regulated T cell balance (Treg > Th17) and reduced clinical disease in the recipient EAE mice. The data presented here provide evidence of the role of GSNO in shifting B cell immune balance (IL-10 > IL-6) and the preclinical relevance of N6022, a first-in-class drug targeting GSNOR with proven human safety, as therapeutics for autoimmune disorders including multiple sclerosis. Elsevier 2021-06-23 /pmc/articles/PMC8246645/ /pubmed/34175668 http://dx.doi.org/10.1016/j.redox.2021.102053 Text en © 2021 The Authors. Published by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Kim, Judong
Islam, S.M. Touhidul
Qiao, Fei
Singh, Avtar K.
Khan, Mushfiquddin
Won, Jeseong
Singh, Inderjit
Regulation of B cell functions by S-nitrosoglutathione in the EAE model
title Regulation of B cell functions by S-nitrosoglutathione in the EAE model
title_full Regulation of B cell functions by S-nitrosoglutathione in the EAE model
title_fullStr Regulation of B cell functions by S-nitrosoglutathione in the EAE model
title_full_unstemmed Regulation of B cell functions by S-nitrosoglutathione in the EAE model
title_short Regulation of B cell functions by S-nitrosoglutathione in the EAE model
title_sort regulation of b cell functions by s-nitrosoglutathione in the eae model
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246645/
https://www.ncbi.nlm.nih.gov/pubmed/34175668
http://dx.doi.org/10.1016/j.redox.2021.102053
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