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 Ly6chi monocytes infiltrated into the infarct border zone and differentiated into mature Ly6clo 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)-beta 1 and collagen-4, along with diminished activation of Smad2. Injection of TGF-beta 1 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-beta 1 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;71:743752