Cofilin signaling in hemin-induced microglial activation and inflammation
Cofilin signaling in hemin-induced microglial activation and inflammation
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DOI：
10.1016/j.jneuroim.2017.10.007
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发表时间：
2017-12-15
影响因子：
3.3
通讯作者：
Shah, Zahoor A.
中科院分区：
文献类型：
--
作者：
Bin Sayeed, Muhammad Shandaat;Alhadidi, Qasim;Shah, Zahoor A.
脑出血（ICH）是最严重的中风形式，并且由于小胶质细胞激活引起的炎症反应引起的继发性损伤进一步加剧。这种继发性损伤部分是由于血红素（血红蛋白的内源性分解产物）的毒性作用造成的。 Cofilin 是一种肌动蛋白解聚因子，控制肌动蛋白动力学，之前已被证明参与介导缺血条件下和细菌脂多糖诱导的小胶质细胞激活期间的神经元细胞死亡。关于 ICH 期间释放的极高浓度血红素的有害影响及其对小胶质细胞和随后的丝切蛋白反应的影响的研究有限。因此，进行了研究以研究氯高铁血红素对小胶质细胞活化诱导的炎症的影响以及肌动蛋白丝切蛋白在介导反应中的关键作用。我们观察到，氯化血红素处理的小胶质细胞的丝切蛋白表达和一氧化氮生成呈浓度依赖性增加。在氯高铁血红素治疗后，观察到 iNOS、TNF-α、HO1、Nrf2、Wfs-1、XBP-1 和剪接 XBP-1 水平升高，并且发现该信号传导部分由丝切蛋白介导。急性血红素治疗不会诱发 Ca2+ 信号传导，长期治疗血红素也会导致小胶质细胞对乙酰胆碱诱发的 Ca2+ 信号传导失败。 siRNA 敲低丝切蛋白也减少了乙酰胆碱诱发的 Ca2+ 信号传导。这些研究表明，丝切蛋白信号传导在氯高铁血红素诱导的炎症、氧化应激、内质网应激、小胶质细胞迁移以及激发 Ca2+ 信号传导的能力中非常重要。因此，cofilin 抑制可能是治疗 ICH 等情况下由血红素毒性引发的脑损伤的潜在疗法。
Intracerebral hemorrhage (ICH) is the most severe form of stroke and is further exacerbated by the secondary injury involving inflammatory response due to the activation of microglia. This secondary injury is partly due to the toxic effects of hemin, an endogenous breakdown product of hemoglobin. Cofilin, an actin depolymerizing factor, controls actin dynamics and has been previously shown to be involved in mediating neuronal cell death in ischemic conditions and during bacterial lipopolysaccharide induced microglial activation. There are limited studies regarding the deleterious effects of extremely high concentrations of hemin released during ICH and its effects on microglia and subsequent cofilin response. Therefore, investigations were conducted to study the effects of hemin on microglial activation induced inflammation and the critical role of cofilin in mediating the response. We observed that hemin treated microglia had a concentration dependent increase in cofilin expression and NO production. There were increased levels of iNOS, TNF-alpha, HO1, Nrf2, Wfs-1, XBP-1 and spliced XBP-1 observed in response to hemin treatment and the signaling was found to be partly mediated by cofilin. Acute hemin treatment did not evoke Ca2+ signaling and long-term treatment of hemin also resulted in the failure of microglial response to acetylcholine-evoked Ca2+ signaling. Knockdown of cofilin by siRNA also reduced acetylcholine-evoked Ca2+ signaling. These studies demonstrate that cofilin signaling is important in hemin-induced inflammation, oxidative stress, ER stress, microglial migration, and the ability to evoke Ca2+ signaling. Therefore, cofilin inhibition could be a potential therapy in brain injuries triggered by hemin toxicity in conditions like ICH.