title: Atf6α deficiency suppresses microglial activation and ameliorates pathology of experimental autoimmune encephalomyelitis.
abstract: Accumulating evidence suggests a critical role for the unfolded protein response in multiple sclerosis (MS) and in its animal model, experimental autoimmune encephalomyelitis (EAE). In this study, we investigated the relevance of activating transcription factor 6α (ATF6α), an upstream regulator of part of the unfolded protein response, in EAE. The expressions of ATF6α-target molecular chaperones such as glucose-regulated protein 78 (GRP78) and glucose-regulated protein 94 (GRP94) were enhanced in the acute inflammatory phase after induction of EAE. Deletion of Atf6α suppressed the accumulation of T cells and microglia/macrophages in the spinal cord, and ameliorated the clinical course and demyelination after EAE induction. In contrast to the phenotypes in the spinal cord, activation status of T cells in the peripheral tissues or in the culture system was not different between two genotypes. Bone marrow transfer experiments and adoptive transfer of autoimmune CD4+T cells to recipient mice (passive EAE) also revealed that CNS-resident cells are responsible for the phenotypes observed in Atf6α-/-mice. Further experiments with cultured cells indicated that inflammatory response was reduced in Atf6α-/-microglia, but not in Atf6α-/-astrocytes, and was associated with proteasome-dependent degradation of NF-κB p65. Thus, our results demonstrate a novel role for ATF6α in microglia-mediated CNS inflammation. We investigated the relevance of ATF6α, an upstream regulator of part of the UPR, in EAE. Deletion of Atf6α suppressed inflammation, and ameliorated demyelination after EAE. Bone marrow transfer experiments and adoptive transfer of autoimmune CD4+T cells revealed that CNS-resident cells are responsible for the phenotypes in Atf6α-/-mice. Furthermore, inflammatory response was reduced in Atf6α-/-microglia, and was associated with degradation of NF-κB p65. Our results demonstrate a novel role for ATF6α in microglia-mediated inflammation. Cover image for this issue: doi: 10.1111/jnc.13346.
authors.affiliation: Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Hieu Minh
authors.initials: HM
authors.lastname: Ta
authors.affiliation: Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Thuong Manh
authors.initials: TM
authors.lastname: Le
authors.affiliation: Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishii
authors.affiliation: Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Takarada-Iemata
authors.affiliation: Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hattori
authors.affiliation: Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Hashida
authors.affiliation: Department of Biochemistry and Molecular Vascular Biology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Mori
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kitao
authors.affiliation: Department of Neuroanatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Hori
mesh_terms: D051702:Activating Transcription Factor 6 / Q000172:deficiency*; D000818:Animals; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D000091342:Endoplasmic Reticulum Chaperone BiP; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse
keywords: UPR; inflammation; microglia; multiple sclerosis