期刊
JOURNAL OF IMMUNOLOGY
卷 183, 期 7, 页码 4733-4744出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0803590
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资金
- Spanish Ministry of Science and Innovation [SAF 2006-02178, SAF 2009-07503]
- Ministry of Health, Carlos III Institute [G03/005]
- PNSD [G46923421]
- General Direction of Drug Dependence (GV)
- Fundacion de Investigacion Medica Mutua Madrilena
Microglial cells are the primary immune effector cells in the brain and play a pivotal role in the neuroinflammatory processes associated with a variety of neurological and pathological disorders. Alcohol consumption induces brain damage, although the neuropathological processes are poorly understood. We previously suggested that ethanol promotes inflammatory processes in the brain, up-regulating inflammatory mediators and signaling pathways associated with IIL-1RI/TLR4 receptors. In the present study we investigate whether ethanol induces microglia activation by stimulating TLR4 response and whether this response causes neuronal death and contributes to ethanol-induced neuroinflammatory damage. We demonstrate that ethanol activates microglia and stimulates NF-kappa B, MAPKs, and MyD88-independent (IFN regulatory factor-3, IFN-beta) pathways to trigger the production of inflammatory mediators, causing neuronal death. The inflammatory response induced by ethanol is completely abrogated in microglia of TLR4-deficient mice (TLR4(-/-)), thus supporting the role of these receptors in microglia activation and neuronal death. In accord with the in vitro findings, acute ethanol administration induces microglia activation (CD11b(+) cells) in cerebral cortex of TLR4(+/+) mice, but not in TLR4(-/-) mice. Taken together, our results not only provide the first evidence of the critical role of the TLR4 response in the ethanol-induced microglia activation, but also new insight into the basic mechanisms participating in ethanol-induced neuroinflammatory damage. The Journal of Immunology, 2009, 183: 4733-4744.
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