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Cell Rep. 2015 Apr 28;11(4):592-604. doi: 10.1016/j.celrep.2015.03.053. Epub 2015 Apr 16.

Astrocyte-derived TGF-β1 accelerates disease progression in ALS mice by interfering with the neuroprotective functions of microglia and T cells.

Author information

1
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.
2
Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi 4648601, Japan.
3
Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako, Saitama 3510198, Japan.
4
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 4668550, Japan.
5
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 4668550, Japan; CREST, Japan Science and Technology Agency, Saitama 3320012, Japan.
6
Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 9808575, Japan.
7
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
8
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.

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.

PMID:
25892237
DOI:
10.1016/j.celrep.2015.03.053
[Indexed for MEDLINE]
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