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Cited by 284Neuroinflammation and Neurodegeneration MechanismsAcute Ischemic Stroke ManagementIntracerebral and Subarachnoid Hemorrhage Research

Macrophages prevent hemorrhagic infarct transformation in murine stroke models

Gliem, Michael, Mausberg, Anne Kathrin, Lee, John‐Ih, Simiantonakis, Ioannis, van Rooijen, Nico, Hartung, Hans‐Peter, Jander, Sebastian·2012·Annals of Neurology
DOI 10.1002/ana.23529
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Abstract

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. ANN NEUROL 2012;71:743–752

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  • Monocytes are important in healing after stroke.

    “demonstrating the importance of these cells in healing after stroke”

    From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [127]

  • In CCR2-deficient mice or after early monocyte depletion by clodronate liposomes in stroke, reduced expression of tissue repair proteins including TGF-β1 and collagen-4 is associated with neurovascular unit instability and later haemorrhagic transformation.

    “In CCR2-deficient mice or following early monocyte depletion by clodronate liposomes in stroke, the resultant reduced expression of tissue repair proteins, including TGF-β1 and collagen-4, was associated with neurovascular unit instability and later haemorrhagic transformation [127]”

    From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [127]

  • Depletion of these monocytes has a negative impact on stroke outcome and increases the incidence of hemorrhagic transformation.

    “However, depletion of these cells has a negative impact on stroke outcome and increases the incidence of hemorrhagic transformation (146).”

    From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [146]

  • Pro-inflammatory monocytes eventually follow neutrophils into the brain parenchyma and enter in a CCR2-dependent manner, eventually differentiating into Ly6Clow phagocytes.

    “Pro-inflammatory monocytes eventually follow neutrophils into the brain parenchyma and enter in a CCR2-dependent manner, eventually differentiating into Ly6Clow phagocytes.”

    From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [146]

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Authors
Gliem, M., Mausberg, A. K., Lee, J., Simiantonakis, I., van Rooijen, N., Hartung, H., & Jander, S.
Affiliations
Heinrich Heine University Düsseldorf (DE)
Corresponding author
Jander, Sebastian
ORCID
Venue
Annals of Neurology
Publisher
Wiley
Published
2012-06
Volume
71
Issue
6
Pages
743-752
ISSN
  • 0364-5134 (ISSN-L)
  • 1531-8249
DOI
10.1002/ana.23529
OpenAlex
W2122031395
Cited by
284
References
39
Citations by year
2026: 8 · 2025: 19 · 2024: 19 · 2023: 16 · 2022: 29 · 2021: 19 · 2020: 25 · 2019: 14 · 2018: 21 · 2017: 19 · 2016: 31 · 2015: 29 · 2014: 15 · 2013: 17 · 2012: 3
FWCI
10.26
Type
journal article
Language
en
Open access
closed
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 19 d)
Locations
  • Annals of Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
  • Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
  • Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
Keywords
macrophages, monocytes, ischemic stroke, hemorrhagic transformation, CCR2, TGF-β1, Smad2, neurovascular unit, infarct border zone, bone marrow-derived cells, cell depletion, CX3CR1
MeSH terms
CX3C Chemokine Receptor 1, CD68 Molecule, Animals, Antigens, Ly, Cell Differentiation, Diphtheria Toxin, Disease Models, Animal, Drug Administration Routes, Flow Cytometry, Gene Expression Regulation, Germanium, Interferon Inducers, Macrophages, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Organometallic Compounds, Propionates, Time Factors, Antigens, Differentiation, Myelomonocytic, Antigens, CD, Leukocyte Common Antigens, Receptors, Chemokine, Infarction, Middle Cerebral Artery, Intracranial Hemorrhages, Brain Infarction, Stroke, Intracranial Thrombosis, Intercellular Signaling Peptides and Proteins, CD11b Antigen, Mice, Transforming Growth Factor beta1, Receptors, CCR2, Heparin-binding EGF-like Growth Factor

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