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Glia-dependent TGF-β signaling, acting independently of the TH17 pathway, is critical for initiation of murine autoimmune encephalomyelitis
Jian Luo, … , Lawrence Steinman, Tony Wyss-Coray
Jian Luo, … , Lawrence Steinman, Tony Wyss-Coray
Published October 25, 2007
Citation Information: J Clin Invest. 2007;117(11):3306-3315. https://doi.org/10.1172/JCI31763.
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Research Article Autoimmunity

Glia-dependent TGF-β signaling, acting independently of the TH17 pathway, is critical for initiation of murine autoimmune encephalomyelitis

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Abstract

Autoimmune encephalomyelitis, a mouse model for multiple sclerosis, is characterized by the activation of immune cells, demyelination of axons in the CNS, and paralysis. We found that TGF-β1 synthesis in glial cells and TGF-β–induced signaling in the CNS were activated several days before the onset of paralysis in mice with autoimmune encephalomyelitis. While early production of TGF-β1 was observed in glial cells TGF-β signaling was activated in neurons and later in infiltrating T cells in inflammatory lesions. Systemic treatment with a pharmacological inhibitor of TGF-β signaling ameliorated the paralytic disease and reduced the accumulation of pathogenic T cells and expression of IL-6 in the CNS. Priming of peripheral T cells was not altered, nor was the generation of TH17 cells, indicating that this effect was directed within the brain, yet affected the immune system. These results suggest that early production of TGF-β1 in the CNS creates a permissive and dangerous environment for the initiation of autoimmune inflammation, providing a rare example of the brain modulating the immune system. Importantly, inhibition of TGF-β signaling may have benefits in the treatment of the acute phase of autoimmune CNS inflammation.

Authors

Jian Luo, Peggy P. Ho, Marion S. Buckwalter, Tiffany Hsu, Lowen Y. Lee, Hui Zhang, Dae-Kee Kim, Seong-Jin Kim, Sanjiv S. Gambhir, Lawrence Steinman, Tony Wyss-Coray

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Figure 1

Astrogliosis and neuroinflammation precede clinical signs in EAE.

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Astrogliosis and neuroinflammation precede clinical signs in EAE.
(A and...
(A and B) EAE was induced in GFAP-luc mice with MOG35–55 emulsified in CFA plus PT, and bioluminescence was recorded in living mice (n = 7) injected with luciferin (150 mg/kg) 1 day before (–1) and at 3, 7, 10, or 14 dpi. Time course of bioluminescence recorded in a representative mouse (A) and the bioluminescence expressed as fold induction plotted with clinical score (B). (C) Mice were sacrificed at indicated time points. Sagittal brain sections from control (–1) or EAE mice sacrificed at different time points were examined for neuroinflammation, and images were taken from cerebellum. Neuroinflammation was assessed by immunohistochemistry as a function of astrogliosis (GFAP), microgliosis (CD68), and T lymphocyte infiltration (CD4). Scale bars: 100 μm.

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