Macrophage Plasticity in Experimental Atherosclerosis

As in human disease, macrophages (M empty set) are central players in the development and progression of experimental atherosclerosis. In this study we have evaluated the phenotype of Mempty set associated with progression of atherosclerosis in the apolipoprotein E (ApoE) knockout (KO) mouse model. We found that bone marrow-derived Mempty set submitted to M1 and M2 polarization specifically expressed arginase (Arg) II and Arg I, respectively. This distinct arginase expression was used to evaluate the frequency and distribution of M1 and M2 Mempty set in cross-sections of atherosclerotic plaques of ApoE KO mice. Early lesions were infiltrated by Arg I+ (M2) Mempty set. This type of M empty set favored the proliferation of smooth muscle cells, in vitro. Arg II+ (M1) Mempty set appeared and prevailed in lesions of aged ApoE KO mice and lesion progression was correlated with the dominance of M1 over the M2 Mempty set phenotype. In order to address whether the M2->M1 switch could be due to a phenotypic switch of the infiltrated cells, we performed in vitro repolarization experiments. We found that fully polarized Mempty set retained their plasticity since they could revert their phenotype. The analysis of the distribution of Arg I-and Arg II-expressing Mempty set also argued against a recent recruitment of M1 Mempty set in the lesion. The combined data therefore suggest that the M2->M1 switch observed in vivo is due to a conversion of cells already present in the lesion. Our study suggests that interventional tools able to revert the Mempty set infiltrate towards the M2 phenotype may exert an atheroprotective action.