Xiao-Yi Xiong1, Liang Liu1, Fa-Xiang Wang1, Yuan-Rui Yang1, Jun-Wei Hao1, Peng-Fei Wang1, Qi Zhong1, Kai Zhou1, Ao Xiong1, Wen-Yao Zhu1, Ting Zhao1, Zhao-You Meng1, Yan-Chun Wang1, Qiu-Wen Gong1, Mao-Fan Liao1, Jian Wang1, Qing-Wu Yang2. 1. From Department of Neurology, Xinqiao Hospital, Third Military Medical University, Shapingba District, Chongqing, China (X.-Y.X., L.L., F.-X.W., Y.-R.Y., Q.Z., K.Z., W.-Y.Z., T.Z., Z.-Y.M., Y.-C.W., Q.-W.G., M.-F.L., Q.-W.Y.); Department of Neurology, Key Laboratory of Neurorepair and Regeneration, Tianjin and Ministry of Education, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China (J.-W.H.); Department of Neurology, Weihai Municipal Hospital, Weihai, China (P.-F.W.); Basic Medical College, Zhengzhou University, Zhengzhou, China (A.X.); and Department of Anesthesiology/Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD (J.W.). 2. From Department of Neurology, Xinqiao Hospital, Third Military Medical University, Shapingba District, Chongqing, China (X.-Y.X., L.L., F.-X.W., Y.-R.Y., Q.Z., K.Z., W.-Y.Z., T.Z., Z.-Y.M., Y.-C.W., Q.-W.G., M.-F.L., Q.-W.Y.); Department of Neurology, Key Laboratory of Neurorepair and Regeneration, Tianjin and Ministry of Education, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China (J.-W.H.); Department of Neurology, Weihai Municipal Hospital, Weihai, China (P.-F.W.); Basic Medical College, Zhengzhou University, Zhengzhou, China (A.X.); and Department of Anesthesiology/Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD (J.W.). yangqwmlys@hotmail.com.
Abstract
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.
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-/- ICHmice but aggravated by the humanhepcidin-25 peptide in C57BL/6 ICHmice. 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.
Authors: Che-Feng Chang; Brittany A Goods; Michael H Askenase; Matthew D Hammond; Stephen C Renfroe; Arthur F Steinschneider; Margaret J Landreneau; Youxi Ai; Hannah E Beatty; Luís Henrique Angenendt da Costa; Matthias Mack; Kevin N Sheth; David M Greer; Anita Huttner; Daniel Coman; Fahmeed Hyder; Sourav Ghosh; Carla V Rothlin; J Christopher Love; Lauren H Sansing Journal: J Clin Invest Date: 2017-12-18 Impact factor: 14.808