2. Academic Validation
  3. GRP78 alleviates secondary brain injury by regulating phenotype polarization in astrocytes via JAK2-STAT3 pathway after intracerebral hemorrhage

GRP78 alleviates secondary brain injury by regulating phenotype polarization in astrocytes via JAK2-STAT3 pathway after intracerebral hemorrhage

  • Int Immunopharmacol. 2025 Sep 11:165:115466. doi: 10.1016/j.intimp.2025.115466.
Jiawei Yang 1,  Chengwei Duan 2,  Yan Song 3,  Xiangyang Zhu 4,  Jiabing Shen 5,  Qiuhong Ji 6
Affiliations

Affiliations

  • 1 Suzhou Medical College of Soochow University, Suzhou 215000, China; Department of Neurology, Affiliated Hospital of Nantong University, Nantong 226000, China; Department of Neurology, Affiliated Hospital 2 of Nantong University, Nantong 226000, China. Electronic address: yangjiawei@ntu.edu.cn.
  • 2 Medical Research Center, Affiliated Hospital 2 of Nantong University, Nantong 226000, China.
  • 3 Department of Neurology, Nantong Hospital of Traditional Chinese Medicine, Nantong 226000, China.
  • 4 Department of Neurology, Affiliated Hospital 2 of Nantong University, Nantong 226000, China.
  • 5 Department of Neurology, Affiliated Hospital of Nantong University, Nantong 226000, China. Electronic address: shenjb0818@ntu.edu.cn.
  • 6 Suzhou Medical College of Soochow University, Suzhou 215000, China; Department of Neurology, Affiliated Hospital of Nantong University, Nantong 226000, China. Electronic address: jiqiuhong@ntu.edu.cn.
PMID: 40939434 DOI: 10.1016/j.intimp.2025.115466
Abstract

Background: Astrocytes, exhibiting dual phenotypes (A1 neurotoxic and A2 neuroprotective), play a pivotal role in secondary brain injury (SBI) subsequent to intracerebral hemorrhage (ICH). However, the underlying mechanisms remain elusive. This study sought to explore whether Glucose-regulated protein 78 (GRP78), an essential chaperone involved in endoplasmic reticulum stress, alleviates SBI by influencing astrocytic polarization and to elucidate the underlying mechanisms.

Methods: An autologous blood intracerebral hemorrhage model was established in C57BL/6 mice (8-10 weeks old, 25-30 g), and mouse astrocyte cell line CRL-2541 was exposed to hemin to mimic ICH in vitro. GRP78 small interfering RNAs(siRNAs) were utilized to knock down GRP78, and plasmids were constructed to effectively overexpress GRP78 in CRL-2541 cells. Immunofluorescence, Western blot, immunoprecipitation, CCK-8 assays, and quantitative real-time RT-PCR (qRT-PCR) were evaluated.

Results: It was shown that GRP78 was increased after ICH, peaking at 72 h in vivo and 24 h in vitro. GRP78 knockdown promoted A1 astrocyte expression and suppressed A2 astrocyte expression. Inhibition of GRP78 aggravated hemin-induced cell damage. While GRP78 overexpression significantly promoted astrocytic polarization toward the A2 phenotype, reduced pro-inflammatory cytokine release, and activated the JAK2-STAT3 pathway. Inhibition of the JAK2-STAT3 pathway attenuated the influence of GRP78 on the phenotypic transformation from A1 to A2.

Conclusions: GRP78 alleviates SBI after ICH by promoting astrocytic polarization via JAK2-STAT3 signaling. These findings highlight GRP78 as a potential therapeutic target for SBI caused by ICH.

Keywords

Astrocytic polarization; GRP78; Intracerebral hemorrhage; JAK2-STAT3 pathway; Secondary brain injury.

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