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Atf6α deficiency suppresses microglial activation and ameliorates pathology of experimental autoimmune encephalomyelitis
Author(s) -
Ta Hieu Minh,
Le Thuong Manh,
Ishii Hiroshi,
TakaradaIemata Mika,
Hattori Tsuyoshi,
Hashida Koji,
Yamamoto Yasuhiko,
Mori Kazutoshi,
Takahashi Ryosuke,
Kitao Yasuko,
Hori Osamu
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13714
Subject(s) - experimental autoimmune encephalomyelitis , adoptive cell transfer , microglia , immunology , inflammation , unfolded protein response , atf6 , encephalomyelitis , biology , multiple sclerosis , medicine , immune system , microbiology and biotechnology , t cell , endoplasmic reticulum
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 ( ATF 6α), an upstream regulator of part of the unfolded protein response, in EAE . The expressions of ATF 6α‐target molecular chaperones such as glucose‐regulated protein 78 ( GRP 78) and glucose‐regulated protein 94 ( GRP 94) 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 CD 4 + 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 ATF 6α 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 .