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Journal Article Epublish 16 citations

PubMed: 38287411 DOI: 10.1186/s12974-024-03026-6

SRGN amplifies microglia-mediated neuroinflammation and exacerbates ischemic brain injury.

J Neuroinflammation 21(1):35

Authors: Yi Qian, Lixuan Yang, Jian Chen, Chao Zhou, Ningning Zong, Yang Geng, Shengnan Xia, Haiyan Yang, Xinyu Bao, Yan Chen, Yun Xu

Affiliations

  • Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
  • Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China. Department of Neurology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, 210008, China. Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, 210008, China. Jiangsu Provincial Key Discipline of Neurology, Nanjing, 210008, China. Nanjing Neurology Medical Center, Nanjing, 210008, China.

Abstract

BACKGROUND

Microglia is the major contributor of post-stroke neuroinflammation cascade and the crucial cellular target for the treatment of ischemic stroke. Currently, the endogenous mechanism underlying microglial activation following ischemic stroke remains elusive. Serglycin (SRGN) is a proteoglycan expressed in immune cells. Up to now, the role of SRGN on microglial activation and ischemic stroke is largely unexplored.

METHODS

Srgn knockout (KO), Cd44-KO and wild-type (WT) mice were subjected to middle cerebral artery occlusion (MCAO) to mimic ischemic stroke. Exogenous SRGN supplementation was achieved by stereotactic injection of recombinant mouse SRGN (rSRGN). Cerebral infarction was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Neurological functions were evaluated by the modified neurological severity score (mNSS) and grip strength. Microglial activation was detected by Iba1 immunostaining, morphological analysis and cytokines' production. Neuronal death was examined by MAP2 immunostaining and FJB staining.

RESULTS

The expression of SRGN and its receptor CD44 was significantly elevated in the ischemic mouse brains, especially in microglia. In addition, lipopolysaccharide (LPS) induced SRGN upregulation in microglia in vitro. rSRGN worsened ischemic brain injury in mice and amplified post-stroke neuroinflammation, while gene knockout of Srgn exerted reverse impacts. rSRGN promoted microglial proinflammatory activation both in vivo and in vitro, whereas Srgn-deficiency alleviated microglia-mediated inflammatory response. Moreover, the genetic deletion of Cd44 partially rescued rSRGN-induced excessed neuroinflammation and ischemic brain injury in mice. Mechanistically, SRGN boosted the activation of NF-κB signal, and increased glycolysis in microglia.

CONCLUSION

SRGN acts as a novel therapeutic target in microglia-boosted proinflammatory response following ischemic stroke.

MeSH

Stroke, Brain Injuries, Therapeutics, Genes, Microglia

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