Macrophages prevent hemorrhagic infarct transformation in murine stroke models

Ann Neurol. 2012 Jun;71(6):743-52. doi: 10.1002/ana.23529.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Antigens, Ly / metabolism
  • Brain Infarction / etiology
  • Brain Infarction / prevention & control*
  • CD11b Antigen / genetics
  • CD11b Antigen / metabolism
  • CX3C Chemokine Receptor 1
  • Cell Differentiation
  • Diphtheria Toxin / administration & dosage
  • Disease Models, Animal
  • Drug Administration Routes
  • Flow Cytometry
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology*
  • Heparin-binding EGF-like Growth Factor
  • Infarction, Middle Cerebral Artery / complications
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Interferon Inducers / administration & dosage
  • Intracranial Hemorrhages / etiology
  • Intracranial Hemorrhages / prevention & control*
  • Intracranial Thrombosis / complications
  • Leukocyte Common Antigens / genetics
  • Macrophages / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Activity / physiology
  • Organometallic Compounds / administration & dosage
  • Receptors, CCR2 / deficiency
  • Receptors, Chemokine / genetics
  • Stroke / complications*
  • Stroke / etiology
  • Stroke / pathology*
  • Time Factors
  • Transforming Growth Factor beta1 / administration & dosage
  • Transforming Growth Factor beta1 / metabolism


  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • Antigens, Ly
  • CD11b Antigen
  • CD68 antigen, human
  • CX3C Chemokine Receptor 1
  • Ccr2 protein, mouse
  • Cx3cr1 protein, mouse
  • Diphtheria Toxin
  • HBEGF protein, human
  • Hbegf protein, mouse
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Interferon Inducers
  • Organometallic Compounds
  • Receptors, CCR2
  • Receptors, Chemokine
  • Transforming Growth Factor beta1
  • proxigermanium
  • Leukocyte Common Antigens
  • Ptprc protein, mouse