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

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 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-γ-dominant milieu. Moreover, expression levels of endogenous TGF-β1 in SOD1(G93A) mice negatively correlate with lifespan. Furthermore, pharmacological administration of a TGF-β signaling inhibitor after disease onset extends survival time of SOD1(G93A) mice. These findings indicate that astrocytic TGF-β1 determines disease progression and is critical to the pathomechanism of ALS.

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

“…Consistent with previous work, we observed induction of TGFß and its receptor in SOD1(G86R) mice [23], and these two inductions were blunted in SOD1(G86R) mice lacking the Htr2b gene (Fig 6b). Importantly expression levels of Ly6c1, a cell surface marker expressed on monocytes, but not microglia [9], were unaltered in SOD1(G86R) mice, irrespective of the Htr2b genotype (Fig.…”

Mesenchymal stem cells for the treatment of neurological diseases: Immunoregulation beyond neuroprotection

“…An increased number of microglial cells with an activated status is classically described in brain and spinal cords of subjects deceased due to ALS (reviewed in [90]). A recent report by Endo and coauthors suggests that, in ALS, the phenotype of microglial cells is switched to a detrimental one by astrocytes, thus worsening disease outcome [91]. Mice with a glycine to alanine mutation at amino acid position 93 in the superoxide dismutase gene (SOD-G93A mice) are most commonly used to model human ALS, as they display features similar to human ALS in particular with regard to innate CNS responses.…”

“Targeting astrocytes in CNS injury and disease: A translational research approach”

“…A recent study found that the inflammatory cytokine TNF-α is able to increase the expression of GLT-1 in astrocytes cultured from wild-type rats, but not those cultured from a rat model of ALS (Dumont et al, 2014). Another study has linked astrocytes, inflammation, and ALS pathology, reporting that in both mouse and human ALS, astrocytes have upregulated expression of the anti-inflammatory cytokine transforming growth factor-β1 (TGF-β1), which prevents microglial and T cell production of IGF-1, leading to accelerated disease progression due to the loss of inflammatory-mediated neuroprotection (Endo et al, 2015). Astrocytes from both familial and sporadic ALS patients postmortem have been shown to be toxic to motor neurons (Haidet-Phillips et al, 2011).…”