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.
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.
Authors: Gabriel Courties; Fanny Herisson; Hendrik B Sager; Timo Heidt; Yuxiang Ye; Ying Wei; Yuan Sun; Nicolas Severe; Partha Dutta; Jennifer Scharff; David T Scadden; Ralph Weissleder; Filip K Swirski; Michael A Moskowitz; Matthias Nahrendorf Journal: Circ Res Date: 2014-10-31 Impact factor: 17.367
Authors: Qingkun Liu; Emily M Johnson; Rachel K Lam; Qian Wang; Hong Bo Ye; Edward N Wilson; Paras S Minhas; Ling Liu; Michelle S Swarovski; Stephanie Tran; Jing Wang; Swapnil S Mehta; Xi Yang; Joshua D Rabinowitz; Samuel S Yang; Mehrdad Shamloo; Christoph Mueller; Michelle L James; Katrin I Andreasson Journal: Nat Immunol Date: 2019-07-01 Impact factor: 25.606
Authors: Ryan A Frieler; Yutein Chung; Carolyn G Ahlers; George Gheordunescu; Jianrui Song; Thomas M Vigil; Yatrik M Shah; Richard M Mortensen Journal: Exp Neurol Date: 2017-08-31 Impact factor: 5.330