Related Experiment Video
Updated: Aug 17, 2026
Isolation and Flow Cytometric Assessment of Neuroimmune Interactions in a Mini-Stroke Murine Model
Published on: June 20, 2025
Extracellular CIRP Dysregulates Microglial Efferocytosis in Acute Ischemic Stroke via the TLR4/miR-155/MafB Axis
Dmitriy Lapin1,2, Dilara Aylar1, Archna Sharma1,2
1Center For Immunology and Inflammation, The Feinstein Institutes For Medical Research, Manhasset, New York, USA.
Abstract:
Efferocytosis, the phagocytic clearance of dying cells, by microglia is crucial for limiting neuroinflammation and promoting resolution in ischemic stroke. Extracellular cold-inducible RNA-binding protein (eCIRP) is an inflammatory mediator that impairs macrophage bacterial phagocytosis in sepsis and radiation injury, but its role in microglial efferocytosis in ischemic stroke has not yet been studied. Using a transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke, this study demonstrated that eCIRP is released into the cerebrospinal fluid and microglial expression of the crucial efferocytic receptor MerTK decreases in tMCAO mice. CIRP deficiency significantly improved MerTK expression and microglial efferocytosis in tMCAO mice, reducing brain infarction, inflammation, neurological deficit, and survival in acute stroke. eCIRP induces pro-inflammatory micro-RNA 155 (miR-155) via TLR4, which suppresses its target pro-efferocytic transcription factor MAF bZIP (MafB), downregulating MerTK and the downstream cytoskeletal regulators, to impair microglial efferocytosis. Pharmacological blockade of eCIRP-TLR4 interaction using small peptide C23 attenuates miR-155 induction, restores MerTK expression, rescues microglial efferocytosis, and improves outcomes in tMCAO mice. This study uncovers a previously unknown pathway through which eCIRP signaling impairs neuroprotective efferocytic microglial function in ischemic stroke, suggesting that targeting eCIRP may promote functional recovery after stroke.
Insights
Extracellular cold-inducible RNA-binding protein (eCIRP) impairs microglial efferocytosis in ischemic stroke by reducing MerTK expression. Blocking eCIRP-TLR4 interaction improves outcomes by restoring efferocytosis.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglial efferocytosis is vital for resolving neuroinflammation after ischemic stroke.
- Extracellular cold-inducible RNA-binding protein (eCIRP) is an inflammatory mediator implicated in impaired phagocytosis in other conditions.
- The role of eCIRP in microglial efferocytosis following ischemic stroke remains uninvestigated.
Purpose of the Study:
- To investigate the role of eCIRP in microglial efferocytosis after ischemic stroke.
- To elucidate the molecular mechanisms by which eCIRP affects microglial function.
- To evaluate the therapeutic potential of targeting the eCIRP pathway.
Main Methods:
- Transient middle cerebral artery occlusion (tMCAO) mouse model of ischemic stroke.
- Measurement of eCIRP levels, MerTK expression, and microglial efferocytosis.
- Analysis of microRNA-155 (miR-155) and MAF bZIP (MafB) pathways.
- In vivo blockade of eCIRP-TLR4 interaction using peptide C23.
Main Results:
- eCIRP levels increased, while MerTK expression and microglial efferocytosis decreased in tMCAO mice.
- CIRP deficiency improved MerTK expression, efferocytosis, and stroke outcomes.
- eCIRP induced miR-155 via TLR4, suppressing MafB, downregulating MerTK, and impairing efferocytosis.
- Peptide C23 treatment attenuated miR-155, restored MerTK, rescued efferocytosis, and improved stroke outcomes.
Conclusions:
- eCIRP impairs neuroprotective microglial efferocytosis in ischemic stroke via the TLR4/miR-155/MafB/MerTK pathway.
- Targeting eCIRP-TLR4 interaction represents a promising therapeutic strategy for stroke recovery.
