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Glatiramer acetate treatment negatively regulates type I interferon signaling

OBJECTIVE: Glatiramer acetate (GA; Copaxone), a disease-modifying therapy for multiple sclerosis (MS), promotes development of anti-inflammatory (M2, type II) monocytes that can direct differentiation of regulatory T cells. We investigated the innate immune signaling pathways that participate in GA-...

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Autores principales: Molnarfi, Nicolas, Prod'homme, Thomas, Schulze-Topphoff, Ulf, Spencer, Collin M., Weber, Martin S., Patarroyo, Juan C., Lalive, Patrice H., Zamvil, Scott S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4645172/
https://www.ncbi.nlm.nih.gov/pubmed/26601118
http://dx.doi.org/10.1212/NXI.0000000000000179
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author Molnarfi, Nicolas
Prod'homme, Thomas
Schulze-Topphoff, Ulf
Spencer, Collin M.
Weber, Martin S.
Patarroyo, Juan C.
Lalive, Patrice H.
Zamvil, Scott S.
author_facet Molnarfi, Nicolas
Prod'homme, Thomas
Schulze-Topphoff, Ulf
Spencer, Collin M.
Weber, Martin S.
Patarroyo, Juan C.
Lalive, Patrice H.
Zamvil, Scott S.
author_sort Molnarfi, Nicolas
collection PubMed
description OBJECTIVE: Glatiramer acetate (GA; Copaxone), a disease-modifying therapy for multiple sclerosis (MS), promotes development of anti-inflammatory (M2, type II) monocytes that can direct differentiation of regulatory T cells. We investigated the innate immune signaling pathways that participate in GA-mediated M2 monocyte polarization. METHODS: Monocytes were isolated from myeloid differentiation primary response gene 88 (MyD88)–deficient, Toll-IL-1 receptor domain–containing adaptor inducing interferon (IFN)–β (TRIF)–deficient, IFN-α/β receptor subunit 1 (IFNAR1)–deficient, and wild-type (WT) mice and human peripheral blood. GA-treated monocytes were stimulated with Toll-like receptor ligands, then evaluated for activation of kinases and transcription factors involved in innate immunity, and secretion of proinflammatory cytokines. GA-treated mice were evaluated for cytokine secretion and susceptibility to experimental autoimmune encephalomyelitis. RESULTS: GA-mediated inhibition of proinflammatory cytokine production by monocytes occurred independently of MyD88 and nuclear factor–κB, but was blocked by TRIF deficiency. Furthermore, GA did not provide clinical benefit in TRIF-deficient mice. GA inhibited activation of p38 mitogen-activated protein kinase, an upstream regulator of activating transcription factor (ATF)–2, and c-Jun N-terminal kinase 1, which regulates IFN regulatory factor 3 (IRF3). Consequently, nuclear translocation of ATF-2 and IRF3, components of the IFN-β enhanceosome, was impaired. Consistent with these observations, GA inhibited production of IFN-β in vivo in WT mice, but did not modulate proinflammatory cytokine production by monocytes from IFNAR1-deficient mice. CONCLUSION: Our results demonstrate that GA inhibits the type I IFN pathway in M2 polarization of monocytes independently of MyD88, providing an important mechanism connecting innate and adaptive immune modulation in GA therapy and valuable insight regarding its potential use with other MS treatments.
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spelling pubmed-46451722015-11-23 Glatiramer acetate treatment negatively regulates type I interferon signaling Molnarfi, Nicolas Prod'homme, Thomas Schulze-Topphoff, Ulf Spencer, Collin M. Weber, Martin S. Patarroyo, Juan C. Lalive, Patrice H. Zamvil, Scott S. Neurol Neuroimmunol Neuroinflamm Article OBJECTIVE: Glatiramer acetate (GA; Copaxone), a disease-modifying therapy for multiple sclerosis (MS), promotes development of anti-inflammatory (M2, type II) monocytes that can direct differentiation of regulatory T cells. We investigated the innate immune signaling pathways that participate in GA-mediated M2 monocyte polarization. METHODS: Monocytes were isolated from myeloid differentiation primary response gene 88 (MyD88)–deficient, Toll-IL-1 receptor domain–containing adaptor inducing interferon (IFN)–β (TRIF)–deficient, IFN-α/β receptor subunit 1 (IFNAR1)–deficient, and wild-type (WT) mice and human peripheral blood. GA-treated monocytes were stimulated with Toll-like receptor ligands, then evaluated for activation of kinases and transcription factors involved in innate immunity, and secretion of proinflammatory cytokines. GA-treated mice were evaluated for cytokine secretion and susceptibility to experimental autoimmune encephalomyelitis. RESULTS: GA-mediated inhibition of proinflammatory cytokine production by monocytes occurred independently of MyD88 and nuclear factor–κB, but was blocked by TRIF deficiency. Furthermore, GA did not provide clinical benefit in TRIF-deficient mice. GA inhibited activation of p38 mitogen-activated protein kinase, an upstream regulator of activating transcription factor (ATF)–2, and c-Jun N-terminal kinase 1, which regulates IFN regulatory factor 3 (IRF3). Consequently, nuclear translocation of ATF-2 and IRF3, components of the IFN-β enhanceosome, was impaired. Consistent with these observations, GA inhibited production of IFN-β in vivo in WT mice, but did not modulate proinflammatory cytokine production by monocytes from IFNAR1-deficient mice. CONCLUSION: Our results demonstrate that GA inhibits the type I IFN pathway in M2 polarization of monocytes independently of MyD88, providing an important mechanism connecting innate and adaptive immune modulation in GA therapy and valuable insight regarding its potential use with other MS treatments. Lippincott Williams & Wilkins 2015-11-09 /pmc/articles/PMC4645172/ /pubmed/26601118 http://dx.doi.org/10.1212/NXI.0000000000000179 Text en © 2015 American Academy of Neurology This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (http://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.
spellingShingle Article
Molnarfi, Nicolas
Prod'homme, Thomas
Schulze-Topphoff, Ulf
Spencer, Collin M.
Weber, Martin S.
Patarroyo, Juan C.
Lalive, Patrice H.
Zamvil, Scott S.
Glatiramer acetate treatment negatively regulates type I interferon signaling
title Glatiramer acetate treatment negatively regulates type I interferon signaling
title_full Glatiramer acetate treatment negatively regulates type I interferon signaling
title_fullStr Glatiramer acetate treatment negatively regulates type I interferon signaling
title_full_unstemmed Glatiramer acetate treatment negatively regulates type I interferon signaling
title_short Glatiramer acetate treatment negatively regulates type I interferon signaling
title_sort glatiramer acetate treatment negatively regulates type i interferon signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4645172/
https://www.ncbi.nlm.nih.gov/pubmed/26601118
http://dx.doi.org/10.1212/NXI.0000000000000179
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