ORIGINAL RESEARCH Arginase II Promotes Macrophage Inflammatory Responses Through Mitochondrial Reactive Oxygen Species, Contributing to Insulin

Background—-Macrophage-mediated chronic inflammation is mechanistically linked to insulin resistance and atherosclerosis. Although arginase I is considered antiinflammatory, the role of arginase II (Arg-II) in macrophage function remains elusive. This study characterizes the role of Arg-II in macrophage inflammatory responses and its impact on obesity-linked type II diabetes mellitus and atherosclerosis. Methods and Results—-In human monocytes, silencing Arg-II decreases the monocytes ’ adhesion to endothelial cells and their production of proinflammatory mediators stimulated by oxidized low-density lipoprotein or lipopolysaccharides, as evaluated by real-time quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Macrophages differentiated from bone marrow cells of Arg-II–deficient (Arg-II−/−) mice express lower levels of lipopolysaccharide-induced proin-flammatory mediators than do macrophages of wild-type mice. Importantly, reintroducing Arg-II cDNA into Arg-II−/ − macrophages restores the inflammatory responses, with concomitant enhancement of mitochondrial reactive oxygen species. Scavenging of re-active oxygen species by N-acetylcysteine prevents the Arg-II–mediated inflammatory responses. Moreover, high-fat diet–induced infiltration of macrophages in various organs and expression of proinflammatory cytokines in adipose tissue are blunted in Arg-II−/ − mice. Accordingly, Arg-II−/ − mice reveal lower fasting blood glucose and improved glucose tolerance and insulin sensitivity. Furthermore, apolipoprotein E (ApoE)–deficient mice with Arg-II deficiency (ApoE−/−Arg-II−/−) display reduced lesion size with char-acteristics of stable plaques, such as decreased macrophage inflammation and necrotic core. In vivo adoptive transfer experiment