title: Astrocyte-derived TGF-β1 accelerates disease progression in ALS mice by interfering with the neuroprotective functions of microglia and T cells.
abstract: Neuroinflammation, which includes both neuroprotective and neurotoxic reactions by activated glial cells and infiltrated immune cells, is involved in the pathomechanism of amyotrophic lateral sclerosis (ALS). However, the cytokines that regulate the neuroprotective inflammatory response in ALS are not clear. Here, we identify transforming growth factor-β1 (TGF-β1), which is upregulated in astrocytes of murine and human ALS, as a negative regulator of neuroprotective inflammatory response. We demonstrate that astrocyte-specific overproduction of TGF-β1 in SOD1(G93A) mice accelerates disease progression in a non-cell-autonomous manner, with reduced IGF-I production in deactivated microglia and fewer T cells with an IFN-γ-dominant milieu. Moreover, expression levels of endogenous TGF-β1 in SOD1(G93A) mice negatively correlate with lifespan. Furthermore, pharmacological administration of a TGF-β signaling inhibitor after disease onset extends survival time of SOD1(G93A) mice. These findings indicate that astrocytic TGF-β1 determines disease progression and is critical to the pathomechanism of ALS.
authors.affiliation: Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi 4648601, Japan; Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako, Saitama 3510198, Japan; Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 9808575, Japan.
authors.forename: Fumito
authors.initials: F
authors.lastname: Endo
authors.affiliation: Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi 4648601, Japan.
authors.forename: Okiru
authors.initials: O
authors.lastname: Komine
authors.affiliation: Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako, Saitama 3510198, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Fujimori-Tonou
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 4668550, Japan.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.affiliation: Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi 4648601, Japan.
authors.forename: Shijie
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi 4648601, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 4668550, Japan; CREST, Japan Science and Technology Agency, Saitama 3320012, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.affiliation: Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 9808575, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Dezawa
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Wyss-Coray
authors.affiliation: Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi 4648601, Japan; Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako, Saitama 3510198, Japan; CREST, Japan Science and Technology Agency, Saitama 3320012, Japan. Electronic address: kojiyama@riem.nagoya-u.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanaka
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002478:Cells, Cultured; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013601:T-Lymphocytes / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C000606290:SOD1 protein, human; D053773:Transforming Growth Factor beta1; D007371:Interferon-gamma; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1