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

73Citations
Citations of this article
118Readers
Mendeley users who have this article in their library.

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 inSOD1<sup>G93A</sup> 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 SOD1<sup>G93A</sup> mice negatively correlate with lifespan. Furthermore, pharmacological administration of a TGF-β signaling inhibitor after disease onset extends survival time of SOD1<sup>G93A</sup> mice. These findings indicate that astrocytic TGF-β1 determines disease progression and is critical to the pathomechanism of ALS.

Cite

CITATION STYLE

APA

Endo, F., Komine, O., Fujimori-Tonou, N., Katsuno, M., Jin, S., Watanabe, S., … Yamanaka, K. (2015). Astrocyte-Derived TGF-β1 Accelerates Disease Progression in ALS Mice by Interfering with the Neuroprotective Functions of Microglia and T Cells. Cell Reports, 11(4), 592–604. https://doi.org/10.1016/j.celrep.2015.03.053

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free