TLR4/MyD88 Mediated Signaling of Hepcidin Expression Causing Brain Iron Accumulation, Oxidative Injury, and Cognitive Impairment After Intracerebral Hemorrhage
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 ICH patients. 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 improvement of brain iron efflux, oxidative brain injury and cognition impairment was found in Hepc-/- ICH mice, while aggravated by the human hepcidin-25 peptide in C57BL/6 ICH mice. Data obtained in in vitro studies showed that increased hepcidin inhibited brain microvascular endothelial cells' (BMVECs) intracellular iron efflux but was rescued by a hepcidin antagonist, fursultiamine. Using parabiosis ICH models also shows that increased serum hepcidin prevents brain iron efflux. Additionally, TLR4/MyD88 signalling pathway increased hepcidin expression via promoting IL-6 expression and STAT3 phosphorylation. TLR4-/- and MyD88-/- mice exhibited improvement in brain iron efflux at 7, 14 and 28 d after ICH, and TLR4 antagonist, TAK242, significantly decreased brain iron levels at day 14 and 28 post-ICH and improved cognition impairment at day 28.
Conclusions—The presented insight that increased hepcidin expression caused by inflammation prevents brain iron efflux via inhibition of BMVECs' intracellular iron efflux 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 attenuate oxidative brain injury after ICH.
- Received February 4, 2016.
- Revision received July 11, 2016.
- Accepted July 27, 2016.