title: Glatiramer acetate treatment negatively regulates type I interferon signaling.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology and Program in Immunology (N.M., T.P., U.S.-T., C.M.S., J.C.P., S.S.Z.), University of California, San Francisco; the Institute of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; the Department of Pathology and Immunology (P.H.L.), Faculty of Medicine, University of Geneva; and the Department of Neurosciences (P.H.L.), Division of Neurology, University Hospital of Geneva, Switzerland. N.M. is currently affiliated with the Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, and Department of Neurosciences, Division of Neurology, University Hospital of Geneva, Switzerland. T.P. is currently affiliated with Momenta Pharmaceuticals, Cambridge, MA. U.S.-T. is currently affiliated with Silence Therapeutics GmbH, Berlin, Germany. J.C.P. is currently affiliated with Vedanta Biosciences, Inc., Cambridge, MA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Molnarfi
authors.affiliation: Department of Neurology and Program in Immunology (N.M., T.P., U.S.-T., C.M.S., J.C.P., S.S.Z.), University of California, San Francisco; the Institute of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; the Department of Pathology and Immunology (P.H.L.), Faculty of Medicine, University of Geneva; and the Department of Neurosciences (P.H.L.), Division of Neurology, University Hospital of Geneva, Switzerland. N.M. is currently affiliated with the Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, and Department of Neurosciences, Division of Neurology, University Hospital of Geneva, Switzerland. T.P. is currently affiliated with Momenta Pharmaceuticals, Cambridge, MA. U.S.-T. is currently affiliated with Silence Therapeutics GmbH, Berlin, Germany. J.C.P. is currently affiliated with Vedanta Biosciences, Inc., Cambridge, MA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Prod'homme
authors.affiliation: Department of Neurology and Program in Immunology (N.M., T.P., U.S.-T., C.M.S., J.C.P., S.S.Z.), University of California, San Francisco; the Institute of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; the Department of Pathology and Immunology (P.H.L.), Faculty of Medicine, University of Geneva; and the Department of Neurosciences (P.H.L.), Division of Neurology, University Hospital of Geneva, Switzerland. N.M. is currently affiliated with the Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, and Department of Neurosciences, Division of Neurology, University Hospital of Geneva, Switzerland. T.P. is currently affiliated with Momenta Pharmaceuticals, Cambridge, MA. U.S.-T. is currently affiliated with Silence Therapeutics GmbH, Berlin, Germany. J.C.P. is currently affiliated with Vedanta Biosciences, Inc., Cambridge, MA.
authors.forename: Ulf
authors.initials: U
authors.lastname: Schulze-Topphoff
authors.affiliation: Department of Neurology and Program in Immunology (N.M., T.P., U.S.-T., C.M.S., J.C.P., S.S.Z.), University of California, San Francisco; the Institute of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; the Department of Pathology and Immunology (P.H.L.), Faculty of Medicine, University of Geneva; and the Department of Neurosciences (P.H.L.), Division of Neurology, University Hospital of Geneva, Switzerland. N.M. is currently affiliated with the Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, and Department of Neurosciences, Division of Neurology, University Hospital of Geneva, Switzerland. T.P. is currently affiliated with Momenta Pharmaceuticals, Cambridge, MA. U.S.-T. is currently affiliated with Silence Therapeutics GmbH, Berlin, Germany. J.C.P. is currently affiliated with Vedanta Biosciences, Inc., Cambridge, MA.
authors.forename: Collin M
authors.initials: CM
authors.lastname: Spencer
authors.affiliation: Department of Neurology and Program in Immunology (N.M., T.P., U.S.-T., C.M.S., J.C.P., S.S.Z.), University of California, San Francisco; the Institute of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; the Department of Pathology and Immunology (P.H.L.), Faculty of Medicine, University of Geneva; and the Department of Neurosciences (P.H.L.), Division of Neurology, University Hospital of Geneva, Switzerland. N.M. is currently affiliated with the Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, and Department of Neurosciences, Division of Neurology, University Hospital of Geneva, Switzerland. T.P. is currently affiliated with Momenta Pharmaceuticals, Cambridge, MA. U.S.-T. is currently affiliated with Silence Therapeutics GmbH, Berlin, Germany. J.C.P. is currently affiliated with Vedanta Biosciences, Inc., Cambridge, MA.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Weber
authors.affiliation: Department of Neurology and Program in Immunology (N.M., T.P., U.S.-T., C.M.S., J.C.P., S.S.Z.), University of California, San Francisco; the Institute of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; the Department of Pathology and Immunology (P.H.L.), Faculty of Medicine, University of Geneva; and the Department of Neurosciences (P.H.L.), Division of Neurology, University Hospital of Geneva, Switzerland. N.M. is currently affiliated with the Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, and Department of Neurosciences, Division of Neurology, University Hospital of Geneva, Switzerland. T.P. is currently affiliated with Momenta Pharmaceuticals, Cambridge, MA. U.S.-T. is currently affiliated with Silence Therapeutics GmbH, Berlin, Germany. J.C.P. is currently affiliated with Vedanta Biosciences, Inc., Cambridge, MA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Patarroyo
authors.affiliation: Department of Neurology and Program in Immunology (N.M., T.P., U.S.-T., C.M.S., J.C.P., S.S.Z.), University of California, San Francisco; the Institute of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; the Department of Pathology and Immunology (P.H.L.), Faculty of Medicine, University of Geneva; and the Department of Neurosciences (P.H.L.), Division of Neurology, University Hospital of Geneva, Switzerland. N.M. is currently affiliated with the Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, and Department of Neurosciences, Division of Neurology, University Hospital of Geneva, Switzerland. T.P. is currently affiliated with Momenta Pharmaceuticals, Cambridge, MA. U.S.-T. is currently affiliated with Silence Therapeutics GmbH, Berlin, Germany. J.C.P. is currently affiliated with Vedanta Biosciences, Inc., Cambridge, MA.
authors.forename: Patrice H
authors.initials: PH
authors.lastname: Lalive
authors.affiliation: Department of Neurology and Program in Immunology (N.M., T.P., U.S.-T., C.M.S., J.C.P., S.S.Z.), University of California, San Francisco; the Institute of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; the Department of Pathology and Immunology (P.H.L.), Faculty of Medicine, University of Geneva; and the Department of Neurosciences (P.H.L.), Division of Neurology, University Hospital of Geneva, Switzerland. N.M. is currently affiliated with the Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, and Department of Neurosciences, Division of Neurology, University Hospital of Geneva, Switzerland. T.P. is currently affiliated with Momenta Pharmaceuticals, Cambridge, MA. U.S.-T. is currently affiliated with Silence Therapeutics GmbH, Berlin, Germany. J.C.P. is currently affiliated with Vedanta Biosciences, Inc., Cambridge, MA.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Zamvil