Toll-Like Receptor 4/MyD88-Mediated Signaling of Hepcidin Expression Causing Brain Iron Accumulation, Oxidative Injury, and Cognitive Impairment After Intracerebral Hemorrhage
Toll-Like Receptor 4/MyD88-Mediated Signaling of Hepcidin Expression Causing Brain Iron Accumulation, Oxidative Injury, and Cognitive Impairment After Intracerebral Hemorrhage
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Toll 样受体 4/MyD88 介导的铁调素表达信号传导导致脑内铁积累、氧化损伤和脑出血后认知障碍
DOI：
10.1161/circulationaha.116.021881
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发表时间：
2016-10-04
期刊：
影响因子：
37.8
通讯作者：
Yang, Qing-Wu
中科院分区：
文献类型：
--
作者：
Xiong, Xiao-Yi;Liu, Liang;Yang, Qing-Wu
背景：脑出血(ICH)后脑铁代谢紊乱导致氧化性脑损伤和认知功能障碍。海普西丁在调节铁代谢中起着重要作用，我们已报道血清海普西丁与脑出血患者的不良预后呈正相关。然而，海普西丁在脑出血后脑内铁代谢中的作用尚不清楚。方法：采用异育和脑出血动物模型，结合体内和体外实验，研究海普西丁在脑出血后脑铁代谢中的作用。HepC(-/-)脑出血小鼠的脑铁外流、氧化性脑损伤和认知功能障碍均得到改善，而C57BL/6脑出血小鼠的脑铁外流、脑氧化损伤和认知功能障碍则被人海普西丁-25肽加重。体外研究数据显示，增加的海普西丁抑制脑微血管内皮细胞的铁外流，但可被海普西丁拮抗剂呋喃硫胺所拯救。使用异种共生的脑出血模型也表明，血清中海普西丁的增加可以防止脑内铁外流。此外，Toll样受体4(TLR4)/MyD88信号通路通过促进IL-6的表达和信号转导与转录激活因子3的磷酸化，促进了海普西丁的表达。TLR4(-/-)和MyD88(-/-)小鼠脑出血后第7、14和28天脑铁外流明显改善，TLR4拮抗剂(6R)-6-[N-(2-氯-4-氟苯基)磺酰基]环己烯-1-羧酸酯显著降低脑出血后第14天和第28天的脑铁水平，并改善第28天的认知功能障碍。结论：炎症引起的海人球蛋白表达增加可能通过抑制脑微血管内皮细胞内铁外流进入循环，加重脑内氧化损伤和认知功能障碍，从而阻止脑铁外流。确定了抑制炎症、促进脑铁外流和减轻脑出血后氧化性脑损伤的机制靶点。
BACKGROUND: Disturbance of brain iron metabolism after intracerebral hemorrhage (ICH) results in oxidative brain injury and cognition impairment. Hepcidin plays an important role in regulating iron metabolism, and we have reported that serum hepcidin is positively correlated with poor outcomes in patients with ICH. However, the roles of hepcidin in brain iron metabolism after ICH remain largely unknown.METHODS: Parabiosis and ICH models combined with in vivo and in vitro experiments were used to investigate the roles of hepcidin in brain iron metabolism after ICH.RESULTS: Increased hepcidin-25 was found in serum and primarily in astrocytes after ICH. The brain iron efflux, oxidative brain injury, and cognition impairment were improved in Hepc(-/-) ICH mice but aggravated by the human hepcidin-25 peptide in C57BL/6 ICH mice. Data obtained in in vitro studies showed that increased hepcidin inhibited the intracellular iron efflux of brain microvascular endothelial cells but was rescued by a hepcidin antagonist, fursultiamine. Using parabiosis ICH models also shows that increased serum hepcidin prevents brain iron efflux. In addition, Toll-like receptor 4 (TLR4)/MyD88 signaling pathway increased hepcidin expression by promoting interleukin-6 expression and signal transducer and activator of transcription 3 phosphorylation. TLR4(-/-) and MyD88(-/-) mice exhibited improvement in brain iron efflux at 7, 14, and 28 days after ICH, and the TLR4 antagonist (6R)-6-[N-(2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate significantly decreased brain iron levels at days 14 and 28 after ICH and improved cognition impairment at day 28.CONCLUSIONS: The results presented here show that increased hepcidin expression caused by inflammation prevents brain iron efflux via inhibition of the intracellular iron efflux of brain microvascular endothelial cells entering into circulation and aggravating oxidative brain injury and cognition impairment, which identifies a mechanistic target for muting inflammation to promote brain iron efflux and to attenuate oxidative brain injury after ICH.