Interleukin-1 and the interleukin-1 type 1 receptor are essential for the progressive neurodegeneration that ensues subsequent to a mild hypoxic/ischemic injury
Interleukin-1 and the interleukin-1 type 1 receptor are essential for the progressive neurodegeneration that ensues subsequent to a mild hypoxic/ischemic injury
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DOI：
10.1038/sj.jcbfm.9600002
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发表时间：
2005-01-01
影响因子：
6.3
通讯作者：
Levison, SW
中科院分区：
文献类型：
--
作者：
Basu, A;Lazovic, J;Levison, SW
过度的炎症与包括脑缺血在内的多种神经系统疾病中发生的进行性神经变性有关，并且促炎细胞因子白细胞介素-1（IL-1）的水平升高已被证明会加剧脑损伤，而IL-1水平降低会限制损伤的程度。然而，迄今为止，关于哪种受体介导IL-1的有害作用还没有达成共识。因为我们以前已经证明，通过IL-1 1型受体（IL-1 R1）的信号传导是小胶质细胞活化所必需的，并且因为其他研究的结果表明小胶质细胞是神经退行性变的效应物，所以我们假设灭活IL-1 R1将降低缺氧缺血（H/I）损伤引起的损伤程度。研究表明，轻度损伤会引发进行性神经变性，导致囊性梗死，这可以通过灭活IL-1 R1来预防。IL-1 R1缺失小鼠在1个月的恢复期也显示出保留的感觉运动功能。轻度损伤诱导多种促炎细胞因子并激活小胶质细胞，这些反应在缺乏IL-1 R1的小鼠中显着减少。重要的是，神经炎症先于梗塞的进行性扩大，这表明炎症是脑损伤的因果关系，而不是后果。这些发现表明，消除轻度H/I损伤后的炎症将防止脑损伤并保护神经功能。此外，这些数据表明IL-1 R1是主要的促炎细胞因子受体。
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.