Macrophages prevent hemorrhagic infarct transformation in murine stroke models.
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.


CONCLUSIONS
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.
Departments of Neurology, Heinrich Heine University, Medical Faculty, Moorenstrasse 5, Düsseldorf, Germany.
Michael
M
Gliem
Anne Kathrin
AK
Mausberg
John-Ih
JI
Lee
Ioannis
I
Simiantonakis
Nico
N
van Rooijen
Hans-Peter
HP
Hartung
Sebastian
S
Jander
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control*; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D002454:Cell Differentiation; D004167:Diphtheria Toxin / Q000008:administration & dosage; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005857:Germanium; D066257:Heparin-binding EGF-like Growth Factor; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007369:Interferon Inducers / Q000008:administration & dosage; D020300:Intracranial Hemorrhages / Q000209:etiology / Q000517:prevention & control*; D020767:Intracranial Thrombosis / Q000150:complications; D017493:Leukocyte Common Antigens / Q000235:genetics; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009942:Organometallic Compounds / Q000008:administration & dosage; D011422:Propionates; D054390:Receptors, CCR2 / Q000172:deficiency; D019707:Receptors, Chemokine / Q000235:genetics; D020521:Stroke / Q000150:complications* / Q000209:etiology / Q000473:pathology*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000008:administration & dosage / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000950:Antigens, Ly; D039481:CD11b Antigen; D000073883:CX3C Chemokine Receptor 1; D004167:Diphtheria Toxin; D005857:Germanium; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D007369:Interferon Inducers; D017493:Leukocyte Common Antigens; D009942:Organometallic Compounds; D011422:Propionates; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D053773:Transforming Growth Factor beta1; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C515335:Ccr2 protein, mouse; C471885:Cx3cr1 protein, mouse; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; C066750:propagermanium; C516770:Ptprc protein, mouse