期刊
JOURNAL OF NEUROSCIENCE
卷 35, 期 16, 页码 6381-6393出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3644-14.2015
关键词
amyotrophic lateral sclerosis; auto immunity; choroid plexus; neurodegeneration; T cells
资金
- European Research Council Grant [232835]
- European Union Seventh Framework Programme through the TargetBrain Consortium [279017]
Amyotrophic lateral sclerosis (ALS) is a devastating fatal motor neuron disease, for which there is currently no cure or effective treatment. In this disease, local neuroinflammation develops along the disease course and contributes to its rapid progression. In several models of CNS pathologies, circulating immune cells were shown to display an indispensable role in the resolution of the neuroinflammatory response. The recruitment of such cells to the CNS involves activation of the choroid plexus (CP) of the brain for leukocyte trafficking, through a mechanism that requires IFN-gamma signaling. Here, we found that in the mutant SOD1(G93 Lambda) (mSOD1) mouse model of ALS, the CP does not support leukocyte trafficking during disease progression, due to a local reduction in IFN-gamma levels. Therapeutic immunization of mSOD1 mice with a myelin-derived peptide led to CP activation, and was followed by the accumulation of immunoregulatory cells, including IL-10-producing monocyte-derived macrophages and Foxp3 (+) regulatory T cells, and elevation of the neurotrophic factors IGF-1 and GDNF in the diseased spinal cord parenchyma. The immunization resulted in the attenuation of disease progression and an increased life expectancy of the mSOD1 mice. Collectively, our results demonstrate that recruitment of immunoregulatory cells to the diseased spinal cord in ALS, needed for fighting off the pathology, can be enhanced by transiently boosting peripheral immunity to myelin antigens.
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