期刊
CELL REPORTS
卷 11, 期 4, 页码 592-604出版社
CELL PRESS
DOI: 10.1016/j.celrep.2015.03.053
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资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan [23111006, 26293208]
- Ministry of Health, Labour and Welfare of Japan
- Japan Intractable Disease Research Foundation
- Daiko Foundation
- ''Inochino-Iro'' ALS research grant
- Grants-in-Aid for Scientific Research [25860252, 26293208, 26117002, 26117001, 26830046] Funding Source: KAKEN
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-beta 1 (TGF-beta 1), 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-b1 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-gamma-dominant milieu. Moreover, expression levels of endogenous TGF-beta 1 in SOD1(G93A) mice negatively correlate with lifespan. Furthermore, pharmacological administration of a TGF-beta signaling inhibitor after disease onset extends survival time of SOD1(G93A) mice. These findings indicate that astrocytic TGF-beta 1 determines disease progression and is critical to the pathomechanism of ALS.
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