Research Paper Volume 12, Issue 21 pp 21161—21185

Tim-3 deteriorates neuroinflammatory and neurocyte apoptosis after subarachnoid hemorrhage through the Nrf2/HMGB1 signaling pathway in rats

Shenquan Guo1, *, , Yuanzhi Li1,2, *, , Boyang Wei1, , Wenchao Liu1, , Ran Li1, , Wenping Cheng1, , Xin Zhang1, , Xuying He1, , Xifeng Li1, , Chuanzhi Duan1, ,

  • 1 The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
  • 2 Department of Neurosurgery, Affiliated Hengyang Hospital, Southern Medical University (Hengyang Central Hospital), Hengyang, China
* Equal contribution

Received: December 13, 2019       Accepted: July 6, 2020       Published: November 7, 2020
How to Cite

Copyright: © 2020 Guo 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.


Inflammation is known to play an important role in early brain injury (EBI) after subarachnoid hemorrhage (SAH). T cell immunoglobulin and mucin domain-3 (Tim-3) has emerged as a critical regulator of adaptive and innate immune responses, and has been identified to play a vital role in certain inflammatory diseases; The present study explored the effect of Tim-3 on inflammatory responses and detailed mechanism in EBI following SAH. We investigated the effects of Tim-3 on SAH models established by endovascular puncture method in Sprague–Dawley rats. The present studies revealed that SAH induced a significant inflammatory response and significantly increased Tim-3 expression. Tim-3-AAV administration aggravated neurocyte apoptosis, brain edema, blood-brain barrier permeability, and neurological dysfunction; significantly inhibited Nrf2 expression; and increased HMGB1 expression and secretion of pro-inflammatory cytokines, such as tumor necrosis factor alpha, interleukin (IL)-1 beta, IL-17, and IL-18. However, Tim-3 siRNA or NK252 administration abolished the pro-inflammatory effects of Tim-3. Our results indicate a function for Tim-3 as a molecular player that links neuroinflammation and brain damage after SAH. We reveal that Tim-3 overexpression deteriorates neuroinflammatory and neurocyte apoptosis after subarachnoid hemorrhage through the Nrf2/HMGB1 signaling pathway in rats.


AAV: adeno-associated virus; ANOVA: analysis of variance; BBB: blood-brain barrier; BWC: Brain water content; CCA: common carotid artery; CD: cluster of differentiation; CNS: central nervous system; DMSO: dimethyl sulfoxide; EBI: early brain injury; ECA: external carotid artery; ELISA: enzyme-linked immunosorbent assay; HMGB1: high mobility group protein B1; H&E: hematoxylin and eosin; HO-1:Hemeoxygenase-1 Iba1: ionized calcium binding adapter molecule1; ICA: Internal carotid artery; IF: immunofluorescence; IHC: Immunohistochemistry; IL: interleukin; NC: negative control; NF-κB: nuclear factor-κB; NK252: N-[5-(2-Furanyl)-1,3,4-oxadiazol-2-yl]-N'-(2-pyridinylmethyl) urea; Nrf2: nuclear factor (erythroid-derived 2)-like 2; PBS: phosphate buffer solution; qRT-PCR: quantitative real-time polymerase chain reaction; SAH: subarachnoid hemorrhage; SEM: standard error of the mean; siRNA: small interfering RNA; TNF: tumor necrosis factor; TUNEL: terminal deoxynucleotidyl transferase-mediated biotinylated-dUTP nick-end labeling; WB: western blotting.