Signaling through MyD88 Regulates Leukocyte Recruitment after Brain Injury
Signaling through MyD88 Regulates Leukocyte Recruitment after Brain Injury
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DOI：
10.4049/jimmunol.181.9.6481
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发表时间：
2008-11-01
影响因子：
4.4
通讯作者：
Owens, Trevor
中科院分区：
文献类型：
--
作者：
Babcock, Alicia A.;Toft-Hansen, Henrik;Owens, Trevor
CNS损伤引起先天性炎症反应，其使浸润的白细胞具有修复和/或加重组织损伤的能力。协调白细胞进入的最初线索仍然不清楚。我们已经使用流式细胞术，以调查是否MyD 88，一个衔接蛋白，从TLR和受体IL-1和IL-18的信号传输，调节白细胞浸润到刺伤内嗅皮层（EC）和轴突变性在失神经海马的网站。我们先前已经建立了白细胞进入失神经海马的动力学。我们现在表明，显着的白细胞进入EC发生在刺伤后3-12小时内。尽管T细胞在8天内表现出小的逐渐增加，但巨噬细胞浸润明显，并在12-24小时内达到峰值。MyD 88缺陷显着减少巨噬细胞和T细胞的招聘刺伤EC和去神经海马损伤后5天。而巨噬细胞和T细胞进入MyD 88缺陷小鼠的去神经海马在8天仍然受损，白细胞浸润到刺伤EC恢复到野生型小鼠中观察到的水平。TNF-α、IL-1 β和CCL 2的转录物在C57 BL/6小鼠中在峰值表达时在刺伤后增加>50倍，在受伤的MyD 88敲除小鼠中严重减少。在TLR 2缺陷或TLR 4突变小鼠中，白细胞募集和基因表达不受影响。在缺乏IL-1 R或IL-18 R的小鼠中未观察到基因表达的显著差异。这些数据表明，MyD 88依赖性信号转导介导CNS损伤后的促炎基因表达和白细胞募集。免疫学杂志，2008，181：6481-6490。
Injury to the CNS provokes an innate inflammatory reaction that engages infiltrating leukocytes with the capacity to repair and/or exacerbate tissue damage. The initial cues that orchestrate leukocyte entry remain poorly defined. We have used flow cytometry to investigate whether MyD88, an adaptor protein that transmits signals from TLRs and receptors for IL-1 and IL-18, regulates leukocyte infiltration into the stab-injured entorhinal cortex (EC) and into sites of axonal degeneration in the denervated hippocampus. We have previously established the kinetics of leukocyte entry into the denervated hippocampus. We now show that significant leukocyte entry into the EC occurs within 3-12 h of stab injury. Whereas T cells showed small, gradual increases over 8 days, macrophage infiltration was pronounced and peaked within 12-24 h. MyD88 deficiency significantly reduced macrophage and T cell recruitment to the stab-injured EC and the denervated hippocampus at 5 days post-injury. Whereas macrophage and T cell entry remained impaired into the denervated hippocampus of MyD88-deficient mice at 8 days, leukocyte infiltration into the stab-injured EC was restored to levels observed in wild-type mice. Transcripts for TNF-alpha, IL-1 beta, and CCL2, which increased >50-fold after stab injury in C57BL/6 mice at the time of peak expression, were severely reduced in injured MyD88 knockout mice. Leukocyte recruitment and gene expression were unaffected in TLR2-deficient or TLR4 mutant mice. No significant differences in gene expression were observed in mice lacking IL-1R or IL-18R. These data show that MyD88-dependent signaling mediates proinflammatory gene expression and leukocyte recruitment after CNS injury. The Journal of Immunology,2008,181: 6481-6490.