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Updated: May 21, 2026
A Mouse Model of Hemorrhagic Transformation Induced by Acute Hyperglycemia Combined with Transient Focal Ischemia
Published on: November 15, 2024
Macrophages prevent hemorrhagic infarct transformation in murine stroke models
Michael Gliem1, Anne Kathrin Mausberg, John-Ih Lee
1Departments of Neurology, Heinrich Heine University, Medical Faculty, Moorenstrasse 5, Düsseldorf, Germany.
Objective:
Inflammation is increasingly viewed as a new therapeutic target in subacute stages of brain infarction. However, apart from causing secondary damage, inflammation could equally promote beneficial lesion remodeling and repair. Distinct subpopulations of monocytes/macrophages (MOs/MPs) may critically determine the outcome of lesion-associated inflammation.
Methods:
We addressed the role of bone marrow-derived MOs/MPs in 2 different mouse models of ischemic stroke using a combined cell-specific depletion, chemokine receptor knockout, bone marrow chimeric, and pharmacological approach.
Results:
Starting within 24 hours of stroke onset, immature Ly6c(hi) monocytes infiltrated into the infarct border zone and differentiated into mature Ly6c(lo) phagocytes within the lesion compartment. MO/MP infiltration was CCR2-dependent, whereas we did not obtain evidence for additional recruitment via CX3CR1. Depletion of circulating MOs/MPs or selective targeting of CCR2 in bone marrow-derived cells caused delayed clinical deterioration and hemorrhagic conversion of the infarctions. Bleeding frequently occurred around thin-walled, dilated neovessels in the infarct border zone and was accompanied by decreased expression of transforming growth factor (TGF)-β1 and collagen-4, along with diminished activation of Smad2. Injection of TGF-β1 into the lesion border zone greatly reduced infarct bleeding in MO/MP-depleted mice.
Interpretation:
Bone marrow-derived MOs/MPs recruited via CCR2 and acting via TGF-β1 are essential for maintaining integrity of the neurovascular unit following brain ischemia. Future therapies should be aimed at enhancing physiological repair functions of CCR2(+) MOs/MPs rather than blocking their hematogenous recruitment.
Insights
Monocytes/macrophages (MOs/MPs) recruited via CCR2 are crucial for brain repair after stroke. Enhancing their beneficial functions, rather than blocking recruitment, may offer new therapeutic strategies for ischemic stroke recovery.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Inflammation plays a dual role in subacute brain infarction, potentially causing damage or promoting repair.
- Monocyte/macrophage (MO/MP) subpopulations critically influence the outcome of inflammation in brain lesions.
Purpose of the Study:
- To investigate the role of bone marrow-derived MOs/MPs in ischemic stroke.
- To determine the mechanisms of MO/MP recruitment and their contribution to lesion repair and integrity.
Main Methods:
- Utilized mouse models of ischemic stroke.
- Employed cell-specific depletion, chemokine receptor knockout, bone marrow chimeras, and pharmacological approaches.
- Analyzed MO/MP infiltration, differentiation, and expression of key molecular factors.
Main Results:
- CCR2-dependent infiltration of immature monocytes into infarct border zones, differentiating into phagocytic MOs/MPs.
- Depletion of MOs/MPs or CCR2 targeting led to delayed deterioration and increased hemorrhagic conversion.
- Reduced transforming growth factor (TGF)-β1 and collagen-4 expression, with TGF-β1 injection mitigating bleeding.
Conclusions:
- Bone marrow-derived MOs/MPs recruited via CCR2 are essential for neurovascular unit integrity post-ischemia.
- These cells exert beneficial effects through TGF-β1 signaling.
- Therapeutic strategies should focus on enhancing CCR2(+) MO/MP repair functions, not blocking recruitment.
