論文 - 詳細
| RRC ID | 87183 |
|---|---|
| 著者 | Okazaki R, Doi T, Hayakawa K, Morioka K, Imamura O, Takishima K, Hamanoue M, Sawada Y, Nagao M, Tanaka S, Ogata T. |
| タイトル | The crucial role of Erk2 in demyelinating inflammation in the central nervous system. |
| ジャーナル | J Neuroinflammation |
| Abstract |
BACKGROUND:Brain inflammation is a crucial component of demyelinating diseases such as multiple sclerosis. Although the initiation of inflammatory processes by the production of cytokines and chemokines by immune cells is well characterized, the processes of inflammatory aggravation of demyelinating diseases remain obscure. Here, we examined the contribution of Erk2, one of the isoforms of the extracellular signal-regulated kinase, to demyelinating inflammation. METHODS:We used the cuprizone-induced demyelinating mouse model. To examine the role of Erk2, we used Nestin-cre-driven Erk2-deficient mice. We also established primary culture of microglia or astrocytes in order to reveal the crosstalk between two cell types and to determine the downstream cascades of Erk2 in astrocytes. RESULTS:First, we found that Erk is especially activated in astrocytes within the corpus callosum before the peak of demyelination (at 4 weeks after the start of cuprizone feeding). Then, we found that in our model, genetic ablation of Erk2 from neural cells markedly preserved myelin structure and motor function as measured by the rota-rod test. While the initial activation of microglia was not altered in Erk2-deficient mice, these mice showed reduced expression of inflammatory mediators at 3-4 model weeks. Furthermore, the subsequent inflammatory glial responses, characterized by accumulation of microglia and reactive astrocytes, were significantly attenuated in Erk2-deficient mice. These data indicate that Erk2 in astrocytes is involved in augmentation of inflammation and gliosis. We also found that activated, cultured microglia could induce Erk2 activation in cultured astrocytes and subsequent production of inflammatory mediators such as Ccl-2. CONCLUSIONS:Our results suggest that Erk2 activation in astrocytes plays a crucial role in aggravating demyelinating inflammation by inducing inflammatory mediators and gliosis. Thus, therapies targeting Erk2 function in glial cells may be a promising approach to the treatment of distinct demyelinating diseases. |
| 巻・号 | 13(1) |
| ページ | 235 |
| 公開日 | 2016-9-5 |
| DOI | 10.1186/s12974-016-0690-8 |
| PII | 10.1186/s12974-016-0690-8 |
| PMID | 27596241 |
| PMC | PMC5011945 |
| MeSH | Animals Anti-Inflammatory Agents, Non-Steroidal / pharmacology Cells, Cultured Cuprizone / toxicity Cytokines / genetics Cytokines / metabolism Demyelinating Autoimmune Diseases, CNS / chemically induced Demyelinating Autoimmune Diseases, CNS / complications* Demyelinating Autoimmune Diseases, CNS / metabolism* Demyelinating Autoimmune Diseases, CNS / pathology Disease Models, Animal Embryo, Mammalian Enzyme Activation / drug effects Female Gene Expression Regulation / drug effects Gene Expression Regulation / genetics Gliosis / etiology* Gliosis / pathology Mice Mice, Inbred C57BL Mice, Transgenic Mitogen-Activated Protein Kinase 1 / genetics Mitogen-Activated Protein Kinase 1 / metabolism* Monoamine Oxidase Inhibitors / toxicity Motor Disorders / etiology Motor Disorders / physiopathology Myelin Basic Protein / genetics Myelin Basic Protein / metabolism Nestin / genetics Nestin / metabolism Neuroglia / chemistry Neuroglia / drug effects Neuroglia / metabolism Neuroglia / pathology Neurons / drug effects Neurons / metabolism Rats Rats, Wistar |
| IF | 5.793 |
| リソース情報 | |
| 実験動物マウス | RBRC02096 |