title: Atorvastatin promotes human monocyte differentiation toward alternative M2 macrophages through p38 mitogen-activated protein kinase-dependent peroxisome proliferator-activated receptor γ activation.
abstract: M1 and M2 macrophages are detectable in human atherosclerotic lesions, and M2 macrophages are present at locations distant from the lipid core in more stable zones of the plaque and appear to exert anti-inflammatory properties on M1 macrophages. Peroxisome proliferator-activated receptor (PPAR) γ promotes the differentiation of monocytes into anti-inflammatory M2 macrophages. Although both statins and PPARγ ligands have been reported to protect against the progression of atherosclerosis, no data are currently available regarding the implication of statins in the alternative differentiation of human monocytes. In the present study, we hypothesized that atorvastatin may exert novel effects to prime human monocytes toward an anti-inflammatory alternative M2 phenotype. To this aim, we first found that abundant M2 markers were expressed in human circulating monocytes after atorvastatin treatment. Moreover, atorvastatin was able to induce PPARγ expression and activation in human monocytes in vivo and in vitro, resulting in priming primary human monocytes differentiation into M2 macrophages with a more pronounced paracrine anti-inflammatory activity in M1 macrophages. Additional data with molecular approaches revealed that p38 mitogen-activated protein kinase (MAPK) but not extracellular signal-regulated kinase (ERK) 1/2 activation was involved in atorvastatin-mediated PPARγ activation and enhanced alternative M2 macrophage phenotype. Collectively, our data demonstrated that atorvastatin promotes human monocyte differentiation toward alternative M2 macrophages via p38 MAPK-dependent PPARγ activation.
authors: Cardiovascular Department, First Hospital Affiliated to Zhengzhou University, Henan 450000, China; Coronary care unit, First Hospital Affiliated to Nanyang Medical College, Henan 473058, China.
authors: Ou
authors: O
authors: Zhang
authors: Cardiovascular Department, First Hospital Affiliated to Zhengzhou University, Henan 450000, China. Electronic address: zh_jenny@yeah.net.
authors: Jinying
authors: J
authors: Zhang
mesh_terms: D000069059:Atorvastatin / Q000008:administration & dosage / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D047495:PPAR gamma / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047495:PPAR gamma; D000069059:Atorvastatin; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Atherosclerosis; Atorvastatin; M2 macrophages; Monocyte; PPARγ; p38 MAPK