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Intrastriatal Injection of Autologous Blood or Clostridial Collagenase as Murine Models of Intracerebral Hemorrhage
Published on: July 3, 2014
Targeting CIRP and IL-6R-mediated microglial inflammation to improve outcomes in intracerebral hemorrhage
Lisha Ye1, Xiaoyan Tang2, Fangming Liu2
1Department of Neurophysiology and Neuropharmacology, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, 9 Seyuan Road, Nantong, Jiangsu 226019, China; Beijing Institute of Brain Disorders, No. 10 Xitoutiao, Beijing 100069, China.
Insights
Cold-inducible RNA-binding protein (CIRP) drives neuroinflammation after intracerebral hemorrhage (ICH) by activating microglia. A novel peptide inhibitor targeting CIRP and IL-6 receptor (IL-6R) reduced inflammation and protected neurons, showing therapeutic potential.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Cold-inducible RNA-binding protein (CIRP) is an emerging inflammatory mediator in neuronal injury.
- Mechanisms of CIRP's contribution to neuroinflammation post-intracerebral hemorrhage (ICH) are not fully understood.
Purpose of the Study:
- Investigate neuron-derived CIRP's role in microglial inflammation via IL-6 receptor (IL-6R) signaling after ICH.
- Evaluate a peptide inhibitor targeting CIRP and IL-6R for therapeutic potential.
Main Methods:
- Single-cell RNA sequencing to identify microglial response pathways.
- In vitro and in vivo testing of Tat-CIRP-CMA (TCC) peptide inhibitor.
- Assessment of TCC effects on neuronal CIRP, microglial activation, inflammation, and phagocytosis.
- Utilized microglia-specific IL-6Rα knockout mice and clinical analysis of ICH patients.
Main Results:
- Neuron-derived CIRP activates microglia via IL-6R/STAT3 signaling, promoting ICH neuroinflammation.
- TCC treatment reduced CIRP release, suppressed microglial activation, and decreased inflammatory cytokines.
- TCC enhanced microglial phagocytosis; IL-6Rα deletion mirrored TCC's neuroprotective effects.
- Elevated peripheral CIRP correlated with infarct volume in human ICH patients.
Conclusions:
- CIRP is pivotal in post-ICH neuroinflammation, acting on microglial IL-6R.
- The TCC peptide inhibitor effectively mitigates CIRP-IL-6R mediated inflammation and offers neuroprotection.
- CIRP is a promising therapeutic target and prognostic biomarker for ICH.
Introduction:
Cold-inducible RNA-binding protein (CIRP) is an emerging inflammatory mediator implicated in neuronal injury following intracerebral hemorrhage (ICH). However, the underlying mechanisms by which CIRP contributes to neuroinflammation remain unclear.
Objectives:
To investigate the role of neuron-derived CIRP in activating microglial inflammation via IL-6 receptor (IL-6R) signaling after ICH and to evaluate the therapeutic potential of targeting CIRP and IL-6R using a designed peptide inhibitor.
Methods:
Single-cell RNA sequencing was performed to identify key genes and pathways involved in microglial responses post-ICH. A peptide inhibitor, Tat-CIRP-CMA (TCC), was designed to target CIRP and IL-6R and tested in both in vitro (oxygen-glucose deprivation model) and in vivo (rat ICH model) systems. The effects of TCC on neuronal CIRP release, microglial activation, inflammation, and phagocytic function were assessed. A microglia-specific IL-6Rα knockout mouse model was used to further validate the functional relevance of the IL-6R/ signal transducer and activator of transcription 3 (STAT3) pathway. Clinical analysis of human ICH patients evaluated the correlation between peripheral CIRP expression and infarct volume.
Results:
Neuron-derived CIRP activates microglia through IL-6R and downstream STAT3 signaling, driving pro-inflammatory responses in ICH. TCC treatment significantly reduced neuronal CIRP release, suppressed microglial activation, and decreased inflammatory cytokine levels. TCC inhibited the IL-6R /STAT3 pathway and enhanced microglial phagocytosis of red blood cells. Microglia-specific IL-6Rα deletion mirrored the anti-inflammatory and neuroprotective effects observed with TCC, reducing hematoma volume and improving sensory and behavioral outcomes. In human ICH patients, elevated peripheral CIRP expression positively correlated with infarct volume, supporting its value as a biomarker for ICH severity and prognosis.
Conclusion:
CIRP plays a pivotal role in post-ICH neuroinflammation by acting on IL-6R in microglia. The TCC peptide inhibitor effectively reduces CIRP-IL-6R mediated inflammation and supports neuroprotection. CIRP represents a promising therapeutic target and biomarker for ICH.
