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SRGN amplifies microglia-mediated neuroinflammation and exacerbates ischemic brain injury
Yi Qian1, Lixuan Yang1, Jian Chen1
1Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
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.
Insights
Serglycin (SRGN) exacerbates ischemic stroke by promoting microglial inflammation via the NF-κB pathway. Targeting SRGN offers a novel therapeutic strategy for stroke treatment by reducing neuroinflammation and brain injury.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Microglia are key players in post-stroke neuroinflammation.
- Understanding microglial activation mechanisms after ischemic stroke is crucial for effective treatment.
- The role of Serglycin (SRGN) in microglial activation and stroke remains largely unknown.
Purpose of the Study:
- To investigate the role of Serglycin (SRGN) in microglial activation and its impact on ischemic stroke.
- To explore SRGN as a potential therapeutic target for stroke.
Main Methods:
- Middle cerebral artery occlusion (MCAO) model in wild-type, Srgn knockout, and Cd44 knockout mice.
- Assessment of cerebral infarction, neurological function, and microglial activation.
- In vitro studies using microglia stimulated with lipopolysaccharide (LPS) and recombinant SRGN (rSRGN).
Main Results:
- SRGN and CD44 expression increased in ischemic brain tissue, particularly in microglia.
- Exogenous SRGN worsened stroke injury and neuroinflammation; Srgn deficiency improved outcomes.
- SRGN promoted microglial pro-inflammatory activation via NF-κB signaling and increased glycolysis.
- CD44 deletion partially mitigated SRGN-induced inflammation and injury.
Conclusions:
- SRGN significantly contributes to post-stroke neuroinflammation by activating microglia.
- SRGN represents a novel therapeutic target for mitigating microglial-driven inflammation in ischemic stroke.
