Reactive Oxygen Species and 12/15-Lipoxygenase Contribute to the Antiproliferative Capacity of Alternatively Activated Myeloid Cells Elicited during Helminth Infection

摘要

Understanding the role of CDllb~+GR-l~+myeloid suppressor cells in the immune suppression and immunoregulation associated with a variety of diseases may provide therapeutic opportunities.In this article,we show,in a model of helminth infection,that CDllb~+GR-l~+myeloid suppressor cells but not CDllb~+F4/80~(high)mature macrophages expanded in the peritoneal cavity of BALB/c mice implanted with Taenia crassiceps.Peritoneal cell populations from early stage-infected animals impaired T cell proliferation by secreting NO.Yet,they lost their ability to secrete NO in the late stage of infection.Concomitantly,their capacity to exert arginase activity and to express mRNAs coding for FIZZ1(found in inflammatory zone 1),Ym,and macrophage galactose-type C-type lectin increased.Furthermore,cells from early stage-infected mice triggered T cells to secrete IFN-gamma and IL-4,whereas in the late stage of infection,they only induced IL-4 production.These data suggest that CDllb~+GR-l~+myeloid suppressor cells displaying an alternative activation phenotype emerged gradually as T.crassiceps infection progressed.Corroborating the alternative activation status in the late stage of infection,the suppressive activity relied on arginase activity,which facilitated the production of reactive oxygen species including H_2O_2 and superoxide.We also document that the suppressive activity of alternative myeloid suppressor cells depended on 12/15-lipoxygenase activation generating lipid mediators,which triggered peroxisome proliferator-activated receptor-gamma.IL-4 and IL-13 signaling contributed to the expansion of myeloid suppressor cells in the peritoneal cavity of T.crassiceps-infected animals and to their antiproliferative activity by allowing arginase and 12/15-lipoxygenase gene expression.