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Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Targeting Microglial C5aR1 with PMX205 Attenuates Neuroinflammation and Improves Neurological Recovery After
Xuan Shi1,2, Xueyan Li1,2, Haojie Ding1,2
1Department of Neurosurgery, Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China.
Abstract:
Activation of microglia and inflammatory response play a central role in the pathological process following intracerebral hemorrhage (ICH). In this study, single-nucleus transcriptomic and proteomic profiling was performed to investigate microglial changes after ICH. A significant upregulation of complement receptor C5aR1 was identified, particularly enriched in microglial subsets exhibiting a pro-inflammatory phenotype. The cellular localization and temporal expression dynamics of C5aR1 were validated by immunofluorescence staining, Western blotting, and quantitative PCR, demonstrating its sustained elevation in microglia after ICH. Pharmacological inhibition with the selective C5aR1 antagonist PMX205 markedly reduced the release of inflammatory cytokines, alleviated neuronal damage, and improved neurological function. Proteomic profiling and subsequent validation suggested that CCR5 may be associated with C5aR1-related inflammatory responses after ICH. Collectively, these findings suggest that C5aR1 serves as a regulatory factor in microglia-mediated neuroinflammation following ICH, and that targeting this pathway may offer a promising therapeutic strategy for hemorrhagic stroke.
Insights
This study reveals that complement receptor C5aR1 (CD88) is upregulated in microglia after intracerebral hemorrhage (ICH). Inhibiting C5aR1 reduces inflammation and brain damage, suggesting it as a therapeutic target for hemorrhagic stroke.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Microglial activation and inflammation are key in intracerebral hemorrhage (ICH) pathology.
- Understanding microglial responses is crucial for developing effective treatments for hemorrhagic stroke.
Purpose of the Study:
- To investigate microglial changes and identify molecular targets following ICH.
- To explore the role of complement receptor C5aR1 (CD88) in ICH-induced neuroinflammation.
Main Methods:
- Single-nucleus transcriptomic and proteomic profiling of microglia post-ICH.
- Validation using immunofluorescence, Western blotting, and quantitative PCR.
- Pharmacological inhibition of C5aR1 using PMX205 in an ICH model.
Main Results:
- Significant upregulation of C5aR1 identified in pro-inflammatory microglia post-ICH.
- C5aR1 expression was sustained in microglia after ICH.
- PMX205 treatment reduced inflammatory cytokines, neuronal damage, and improved neurological function.
- CCR5 was suggested to be associated with C5aR1-mediated inflammation.
Conclusions:
- C5aR1 plays a regulatory role in microglia-driven neuroinflammation following ICH.
- Targeting the C5aR1 pathway presents a potential therapeutic strategy for hemorrhagic stroke.
