TY - JOUR
T1 - Astrocyte-Derived TGF-β1 Accelerates Disease Progression in ALS Mice by Interfering with the Neuroprotective Functions of Microglia and T Cells
AU - Endo, Fumito
AU - Komine, Okiru
AU - Fujimori-Tonou, Noriko
AU - Katsuno, Masahisa
AU - Jin, Shijie
AU - Watanabe, Seiji
AU - Sobue, Gen
AU - Dezawa, Mari
AU - Wyss-Coray, Tony
AU - Yamanaka, Koji
N1 - Funding Information:
The authors thank the Support Unit for Animal Resource Development and Biomaterial Analysis in RIKEN BSI Research Resources Center for supporting animal experiments and fluorescence-activated cell sorting (FACS) analysis, and BSI-Olympus Collaboration Center for supporting morphological analyses. This work was supported by Grants-in-Aid for Scientific Research on Innovative Areas (23111006) and Scientific Research (B) (26293208) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Grant-in-Aid for Research on rare and intractable diseases, the Research Committee on Establishment of Novel Treatments for Amyotrophic Lateral Sclerosis, from the Ministry of Health, Labour and Welfare of Japan; Japan Intractable Disease Research Foundation; Daiko Foundation; and “Inochi-no-Iro” ALS research grant (K.Y.).
Publisher Copyright:
© 2015 The Authors.
PY - 2015/4/28
Y1 - 2015/4/28
N2 - 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 inSOD1G93A mice accelerates disease progression in a non-cell-autonomous manner, with reduced IGF-I production in deactivated microglia and fewer Tcells with an IFN-γ-dominant milieu. Moreover, expression levels of endogenous TGF-β1 in SOD1G93A mice negatively correlate with lifespan. Furthermore, pharmacological administration of a TGF-β signaling inhibitor after disease onset extends survival time of SOD1G93A mice. These findings indicate that astrocytic TGF-β1 determines disease progression and is critical to the pathomechanism of ALS.
AB - 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 inSOD1G93A mice accelerates disease progression in a non-cell-autonomous manner, with reduced IGF-I production in deactivated microglia and fewer Tcells with an IFN-γ-dominant milieu. Moreover, expression levels of endogenous TGF-β1 in SOD1G93A mice negatively correlate with lifespan. Furthermore, pharmacological administration of a TGF-β signaling inhibitor after disease onset extends survival time of SOD1G93A mice. These findings indicate that astrocytic TGF-β1 determines disease progression and is critical to the pathomechanism of ALS.
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U2 - 10.1016/j.celrep.2015.03.053
DO - 10.1016/j.celrep.2015.03.053
M3 - Article
C2 - 25892237
AN - SCOPUS:84928586698
VL - 11
SP - 592
EP - 604
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 4
ER -
