title: Toll-Like Receptor 4/MyD88-Mediated Signaling of Hepcidin Expression Causing Brain Iron Accumulation, Oxidative Injury, and Cognitive Impairment After Intracerebral Hemorrhage.
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.
authors: 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.).
authors: Xiao-Yi
authors: XY
authors: Xiong
authors: 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.).
authors: Liang
authors: L
authors: Liu
authors: 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.).
authors: Fa-Xiang
authors: FX
authors: Wang
authors: 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.).
authors: Yuan-Rui
authors: YR
authors: Yang
authors: 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.).
authors: Jun-Wei
authors: JW
authors: Hao
authors: 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.).
authors: Peng-Fei
authors: PF
authors: Wang
authors: 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.).
authors: Qi
authors: Q
authors: Zhong
authors: 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.).
authors: Kai
authors: K
authors: Zhou
authors: 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.).
authors: Ao
authors: A
authors: Xiong
authors: 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.).
authors: Wen-Yao
authors: WY
authors: Zhu
authors: 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.).
authors: Ting
authors: T
authors: Zhao
authors: 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.).
authors: Zhao-You
authors: ZY
authors: Meng
authors: 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.).
authors: Yan-Chun
authors: YC
authors: Wang
authors: 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.).
authors: Qiu-Wen
authors: QW
authors: Gong
authors: 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.).
authors: Mao-Fan
authors: MF
authors: Liao
authors: 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.).
authors: Jian
authors: J
authors: Wang
authors: 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.
authors: Qing-Wu
authors: QW
authors: Yang
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000150:complications / Q000378:metabolism*; D002543:Cerebral Hemorrhage / Q000378:metabolism*; D060825:Cognitive Dysfunction / Q000209:etiology / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D064451:Hepcidins / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D064451:Hepcidins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D007501:Iron
keywords: hepcidin; inflammation; intracranial hemorrhages; iron