| First Author | Ta HM | Year | 2016 |
| Journal | J Neurochem | Volume | 139 |
| Issue | 6 | Pages | 1124-1137 |
| PubMed ID | 27333444 | Mgi Jnum | J:237956 |
| Mgi Id | MGI:5817555 | Doi | 10.1111/jnc.13714 |
| Citation | Ta HM, et al. (2016) Atf6alpha deficiency suppresses microglial activation and ameliorates pathology of experimental autoimmune encephalomyelitis. J Neurochem 139(6):1124-1137 |
| abstractText | 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 6alpha (ATF6alpha), an upstream regulator of part of the unfolded protein response, in EAE. The expressions of ATF6alpha-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 Atf6alpha 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 Atf6alpha-/- mice. Further experiments with cultured cells indicated that inflammatory response was reduced in Atf6alpha-/- microglia, but not in Atf6alpha-/- astrocytes, and was associated with proteasome-dependent degradation of NF-kappaB p65. Thus, our results demonstrate a novel role for ATF6alpha in microglia-mediated CNS inflammation. We investigated the relevance of ATF6alpha, an upstream regulator of part of the UPR, in EAE. Deletion of Atf6alpha 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 Atf6alpha-/- mice. Furthermore, inflammatory response was reduced in Atf6alpha-/- microglia, and was associated with degradation of NF-kappaB p65. Our results demonstrate a novel role for ATF6alpha in microglia-mediated inflammation. Cover image for this issue: doi: 10.1111/jnc.13346. |
