Astrocyte-Derived TGF-β1 Accelerates Disease Progression in ALS Mice by Interfering with the Neuroprotective Functions of Microglia and T Cells

被引：165

作者：

Endo, Fumito ^{[1
,2
,3
]}

Komine, Okiru ^{[1
]}

Fujimori-Tonou, Noriko ^{[2
]}

Katsuno, Masahisa ^{[4
]}

Jin, Shijie ^{[1
]}

Watanabe, Seiji ^{[1
]}

Sobue, Gen ^{[4
,5
]}

Dezawa, Mari ^{[3
]}

Wyss-Coray, Tony ^{[6
]}

Yamanaka, Koji ^{[1
,2
,5
]}

机构：

[1] Nagoya Univ, Environm Med Res Inst, Dept Neurosci & Pathobiol, Nagoya, Aichi 4648601, Japan

[2] RIKEN, Brain Sci Inst, Lab Motor Neuron Dis, Wako, Saitama 3510198, Japan

[3] Tohoku Univ, Grad Sch Med, Dept Stem Cell Biol & Histol, Sendai, Miyagi 9808575, Japan

[4] Nagoya Univ, Grad Sch Med, Dept Neurol, Nagoya, Aichi 4668550, Japan

[5] Japan Sci & Technol Agcy, CREST, Kawaguchi, Saitama 3320012, Japan

[6] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA

来源：

CELL REPORTS | 2015年 / 11卷 / 04期

关键词：

AMYOTROPHIC-LATERAL-SCLEROSIS; TGF-BETA; PERIPHERAL-NERVE; MOTOR-NEURONS; ANIMAL-MODEL; SURVIVAL; ACTIVATION; INFLAMMATION; DELIVERY; SUPPORT;

D O I：

10.1016/j.celrep.2015.03.053

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：592 / 604

页数：13

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