期刊
JOURNAL OF NEUROIMMUNE PHARMACOLOGY
卷 9, 期 5, 页码 629-641出版社
SPRINGER
DOI: 10.1007/s11481-014-9553-1
关键词
IL-17; Astrocytes; MIP-1 alpha; Src
资金
- National Natural Science Foundation of China [81322048]
- Award for Jiangsu Specially Appointed Professor
- Major State Basic Research Development Program of China (973 Program) [2013CB733800, 2013CB733803]
Neuroinflammation plays critical roles in multiple sclerosis (MS). In addition to the part played by the lymphocytes, the underlying mechanisms could, in part, be also attributed to activation mediated by astrocytes. Macrophage inflammatory protein-1 alpha (MIP-1 alpha) has been implicated in a number of pathological conditions, specifically attributable to its potent chemottractant effects. Its modulation by IL-17, however, has received very little attention. In the present study, we demonstrated IL-17-mediated induction of MIP-1 alpha in rat primary astroctyes through its binding to the cognate IL-17RA. Furthermore, this effect was mediated via the activation of Src, mitogen-activated protein kinases (MAPKs), PI3K/Akt and NF-kB pathways, culminating ultimately into increased expression of MIP-1 alpha. Exposure of primary mouse astrocytes to IL-17 resulted in increased expression of glial fibrillary acidic protein and, this effect was abrogated in cells cultured in presence of the MIP-1 alpha neutralizing antibody, thus underscoring its role in the activation of astrocytes. In vivo relevance of these findings was further corroborated in experimental autoimmune encephalomyelitis mice that demonstrated significantly increased activation of astrocytes with concomitant increased expression of MIP-1 alpha in the corpus callosum compared with control group. Understanding the regulation of MIP-1 alpha expression may provide insights into the development of potential therapeutic targets for neuroinflammation associated with multiple sclerosis.
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