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

Fumito Endo, Okiru Komine, Noriko Fujimori-Tonou, Masahisa Katsuno, Shijie Jin, Seiji Watanabe, Gen Sobue, Mari Dezawa, Tony Wyss-Coray, Koji Yamanaka

Research output: Contribution to journalArticlepeer-review

112 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)592-604
Number of pages13
JournalCell Reports
Volume11
Issue number4
DOIs
Publication statusPublished - 2015 Apr 28

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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