Neutrophil DREAM promotes neutrophil recruitment in vascular inflammation

The interaction between neutrophils and endothelial cells is critical for the pathogenesis of vascular inflammation. However, the regulation of neutrophil adhesive function remains not fully understood. Intravital microscopy demonstrates that neutrophil DREAM promotes neutrophil recruitment to sites of inflammation induced by TNF-alpha but not MIP-2 or fMLP. We observe that neutrophil DREAM represses expression of A20, a negative regulator of NF-kappa B activity, and enhances expression of pro-inflammatory molecules and phosphorylation of I kappa B kinase (IKK) after TNF-alpha stimulation. Studies using genetic and pharmacologic approaches reveal that DREAM deficiency and IKK beta inhibition significantly diminish the ligand-binding activity of beta 2 integrins in TNF-alpha-stimulated neutrophils or neutrophil-like HL-60 cells. Neutrophil DREAM promotes degranulation through IKK beta-mediated SNAP-23 phosphorylation. Using sickle cell disease mice lacking DREAM, we show that hematopoietic DREAM promotes vaso-occlusive events in microvessels following TNF-alpha challenge. Our study provides evidence that targeting DREAM might be a novel therapeutic strategy to reduce excessive neutrophil recruitment in inflammatory diseases.