RT Journal Article
SR Electronic
T1 Glatiramer acetate treatment negatively regulates type I interferon signaling
JF Neurology - Neuroimmunology Neuroinflammation
JO Neurol Neuroimmunol Neuroinflamm
FD Lippincott Williams & Wilkins
SP e179
DO 10.1212/NXI.0000000000000179
VO 2
IS 6
A1 Molnarfi, Nicolas
A1 Prod'homme, Thomas
A1 Schulze-Topphoff, Ulf
A1 Spencer, Collin M.
A1 Weber, Martin S.
A1 Patarroyo, Juan C.
A1 Lalive, Patrice H.
A1 Zamvil, Scott S.
YR 2015
UL http://nn.neurology.org/content/2/6/e179.abstract
AB 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.APC=antigen-presenting cells; BMDM=bone marrow–derived monocytes; cAMPi=intracellular cyclic adenosine 3′,5′-monophosphate; EAE=experimental autoimmune encephalomyelitis; GA=glatiramer acetate; IFN=interferon; IFNAR=type I interferon receptor; IFNAR1=interferon-α/β receptor subunit-1; IL=interleukin; IRF3=interferon regulatory factor 3; JNK1=c-Jun N-terminal kinase 1; LPS=lipopolysaccharide; LTA=lipoteichoic acid; MHC=major histocompatibility complex; MS=multiple sclerosis; MyD88=myeloid differentiation primary response gene 88; NF=nuclear factor; PBS=phosphate-buffered saline; PI3K=phosphoinositide 3-kinase; STAT=signal transducers and activators of transcription; Th=T helper; TLR=Toll-like receptor; TNF=tumor necrosis factor; Treg=regulatory T cells; TRIF=Toll-IL-1 receptor domain–containing adaptor inducing interferon-β; WT=wild-type