Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
J Neurotrauma. 2010 Jun;27(6):1037-46. doi: 10.1089/neu.2009.1229.
We previously reported that tumor necrosis factor-alpha (TNF-alpha) and Fas receptor induce acute cellular injury, tissue damage, and motor and cognitive deficits after controlled cortical impact (CCI) in mice (Bermpohl et al. 2007 ); however, the TNF receptors (TNFR) involved are unknown. Using a CCI model and novel mutant mice deficient in TNFR1/Fas, TNFR2/Fas, or TNFR1/TNFR2/Fas, we tested the hypothesis that the combination of TNFR2/Fas is protective, whereas TNFR1/Fas is detrimental after CCI. Uninjured knockout (KO) mice showed no differences in baseline physiological variables or motor or cognitive function. Following CCI, mice deficient in TNFR2/Fas had worse post-injury motor and Morris water maze (MWM) performance than wild-type (WT) mice (p < 0.05 group effect for wire grip score and MWM performance by repeated measures ANOVA). No differences in motor or cognitive outcome were observed in TNFR1/Fas KO, or in TNFR2 or TNFR1 single KO mice, versus WT mice. Additionally, no differences in propidium iodide (PI)-positive cells (at 6 h) or lesion size (at 14 days) were observed between WT and TNFR1/Fas or TNFR2/Fas KO mice. Somewhat surprisingly, mice deficient in TNFR1/TNFR2/Fas also had PI-positive cells, lesion size, and motor and MWM deficits similar to those of WT mice. These data suggest a protective role for TNFR2/Fas in the pathogenesis of TBI. Further studies are needed to determine whether direct or indirect effects of TNFR1 deletion in TNFR2/Fas KO mice mediate improved functional outcome in TNFR1/TNFR2/Fas KO mice after CCI.
我们之前报道称肿瘤坏死因子-α（TNF-α）和 Fas 受体在小鼠控制性皮质撞击（CCI）后诱导急性细胞损伤、组织损伤以及运动和认知功能障碍（Bermpohl 等人，2007 年）；然而，涉及的 TNF 受体（TNFR）尚不清楚。我们使用 CCI 模型和新型突变小鼠，缺乏 TNFR1/Fas、TNFR2/Fas 或 TNFR1/TNFR2/Fas，检验了以下假说：CCI 后，TNFR2/Fas 的组合具有保护作用，而 TNFR1/Fas 则具有损害作用。未受伤的敲除（KO）小鼠在基线生理变量或运动或认知功能方面没有差异。CCI 后，缺乏 TNFR2/Fas 的小鼠在受伤后的运动和 Morris 水迷宫（MWM）表现比野生型（WT）小鼠更差（通过重复测量 ANOVA 进行的组间效应，在钢丝抓握评分和 MWM 表现上，p < 0.05）。在 TNFR1/Fas KO 或 TNFR2 或 TNFR1 单 KO 小鼠中，与 WT 小鼠相比，在运动或认知结果方面没有差异。此外，在 WT 和 TNFR1/Fas 或 TNFR2/Fas KO 小鼠之间，没有观察到碘化丙啶（PI）阳性细胞（在 6 小时）或损伤大小（在 14 天）的差异。有些出人意料的是，缺乏 TNFR1/TNFR2/Fas 的小鼠也具有 PI 阳性细胞、损伤大小以及与 WT 小鼠相似的运动和 MWM 缺陷。这些数据表明 TNFR2/Fas 在 TBI 的发病机制中具有保护作用。需要进一步的研究来确定 TNFR1 缺失在 TNFR2/Fas KO 小鼠中的直接或间接作用是否介导了 TNFR1/TNFR2/Fas KO 小鼠在 CCI 后的功能改善。
