期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 25, 期 1, 页码 17-29出版社
SAGE PUBLICATIONS INC
DOI: 10.1038/sj.jcbfm.9600002
关键词
cytokines; IL-1; IL-6; inflammation; microglia; stroke; TNF alpha
资金
- NICHD NIH HHS [2P01 HD30704] Funding Source: Medline
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [P01HD030704] Funding Source: NIH RePORTER
Excessive inflammation has been implicated in the progressive neurodegeneration that occurs in multiple neurological diseases, including cerebral ischemia, and elevated levels of the proinflammatory cytokine interleukin-1 (IL-1) have been shown to exacerbate brain damage, whereas diminishing IL-1 levels limits the extent of injury. However, to date there is no consensus regarding which receptor(s) mediates the detrimental effects of IL-1. Because we have previously demonstrated that signaling through the IL-1 type 1 receptor (IL-1R1) is necessary for microglial activation and because results from other studies have implicated microglia as effectors of neurodegeneration, we hypothesized that inactivating the IL-1R1 would decrease the extent of damage caused by a hypoxic-ischemic (H/I) insult. It is shown that a mild insult initiates progressive neurodegeneration that leads to cystic infarcts, which can be prevented by inactivating the IL-1R1. The IL-1R1 null mice also show preserved sensorimotor function at 1 month's recovery. The mild insult induces multiple proinflammatory cytokines and activates microglia, and these responses are dramatically curtailed in mice lacking the IL-1R1. Importantly, the neuroinflammation precedes the progressive enlargement of the infarct, suggesting that the inflammation is causal rather than a consequence of the brain damage. These findings show that abrogating the inflammation consequent to a mild H/I insult will prevent brain damage and preserve neurological function. Additionally, these data incriminate the IL-1R1 as a master proinflammatory cytokine receptor.
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