Research Paper Volume 13, Issue 23 pp 25564—25577
CHIP ameliorates cerebral ischemia-reperfusion injury by attenuating necroptosis and inflammation
- 1 Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China
- 2 Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China
- 3 Institute of Neuroscience, Zhengzhou University, Zhengzhou 450000, Henan, China
Received: September 7, 2021 Accepted: November 24, 2021 Published: December 14, 2021https://doi.org/10.18632/aging.203774
How to Cite
Copyright: © 2021 Yao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Blood reperfusion of ischemic cerebral tissue may cause cerebral ischemia-reperfusion (CIR) injury. Necroptosis and inflammation have been demonstrated to be involved in the disease-related process of CIR injury. The E3 ubiquitin ligase carboxyl terminus of Hsp70-interacting protein (CHIP) can modulate multiple cellular signaling processes, including necroptosis and inflammation. Numerous studies have demonstrated the neuroprotective effects of CHIP on multiple central nervous system (CNS) diseases. However, the effects of CHIP on CIR injury have not been fully explored. We hypothesize that CHIP can exert neuroprotective effects by attenuating necroptosis and inflammation during CIR injury. In the present study, adult wild-type (WT) C57BL/6 mice and CHIP knock-in (KI) mice with a C57BL/6 background and CHIP overexpression in neural tissue underwent middle cerebral artery occlusion (MCAO) surgery to simulate CIR onset. Our data indicated that CHIP expression in the peri-infarct tissue was markedly increased after MCAO surgery. Compared with WT mice, CHIP KI mice significantly improved neurological deficit scores, decreased cerebral infarct volume, and attenuated brain edema and neuronal damage. Meanwhile, CHIP overexpression attenuated necroptosis and inflammation induced by MCAO surgery. These findings indicated that overexpression of CHIP might exert neuroprotective effects by attenuating necroptosis and inflammation during CIR injury, and increasing CHIP levels may be a potential strategy in cerebrovascular disease therapy.
CHIP: carboxyl terminus of Hsp70-interacting protein; CIR: cerebral ischemia-reperfusion; CNS: central nervous system; WT: wild-type; KI: Knock-in; MCAO: middle cerebral artery occlusion; RIPK1: receptor-interacting protein kinase 1; RIPK3: receptor-interacting protein kinase 3; MLKL: mixed lineage kinase domain-like pseudokinase; TNF-α: tumor necrosis factor-α; IL-1β: interleukin-1β; IL-6: interleukin-6; DAMPs: damage-associated molecular patterns; OGD: oxygen-glucose deprivation; RT-PCR: reverse transcription-polymerase chain reaction; TTC: 2,3,5-triphenyltetrazolium chloride; HE: hematoxylin and eosin; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; p-RIPK3: phosphorylated RIPK3; p-MLKL: phosphorylated MLKL; IL-10: interleukin-10; ELISA: enzyme-linked immunosorbent assay; PBS: phosphate buffer saline; RT: room temperature; DAPI: 4′,6-diamidino-2-phenylindole.