Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain
Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain
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DOI：
10.1038/nm.2749
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发表时间：
2012-06-01
期刊：
影响因子：
82.9
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
--
作者：
Shichita, Takashi;Hasegawa, Eiichi;Yoshimura, Akihiko
缺血后炎症反应是脑缺血再灌注损伤过程中的重要环节。然而，激活缺血脑中浸润的巨噬细胞的机制仍有待澄清。在这里，我们证明，从坏死的脑细胞中释放的过氧化物酶（Prx）家族蛋白诱导巨噬细胞中的炎症细胞因子，包括白细胞介素-23的表达，通过激活Toll样受体2（TLR 2）和TLR 4，从而促进神经细胞死亡，即使细胞内的Prx已被证明是神经保护。在缺血核心的细胞外释放的Prxs发生在中风发作后12小时，和细胞外Prxs与抗体的中和抑制炎症细胞因子的表达和梗死体积的增长。与此相反，高迁移率族蛋白1（HMGB 1），一个众所周知的损伤相关的分子模式的分子，被释放前Prx和缺血后巨噬细胞活化的作用有限。因此，我们认为细胞外Prxs是缺血性脑中以前未知的危险信号，其阻断剂是有效的神经保护工具。
Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. However, the mechanism that activates infiltrating macrophages in the ischemic brain remains to be clarified. Here we demonstrate that peroxiredoxin (Prx) family proteins released extracellularly from necrotic brain cells induce expression of inflammatory cytokines including interleukin-23 in macrophages through activation of Toll-like receptor 2 (TLR2) and TLR4, thereby promoting neural cell death, even though intracellular Prxs have been shown to be neuroprotective. The extracellular release of Prxs in the ischemic core occurred 12 h after stroke onset, and neutralization of extracellular Prxs with antibodies suppressed inflammatory cytokine expression and infarct volume growth. In contrast, high mobility group box 1 (HMGB1), a well-known damage-associated molecular pattern molecule, was released before Prx and had a limited role in post-ischemic macrophage activation. We thus propose that extracellular Prxs are previously unknown danger signals in the ischemic brain and that its blocking agents are potent neuroprotective tools.