Neutrophil DREAM Is a Novel Regulator for Beta2 Integrin Function through NF-Kappab Signaling and Modulates Neutrophil Recruitment during Vascular Inflammation

Abstract

The interaction between neutrophils and activated endothelial cells (ECs) is critical for the pathogenesis of vascular inflammation. However, it remains poorly understood how the cell-cell interactions are regulated under inflammatory conditions. Using intravital microscopy in mice lacking DREAM (downstream regulatory element antagonist modulator), a member of the neuronal Ca2+ sensors and a transcriptional repressor, we have found that DREAM plays an important role in neutrophil rolling and adhesion to the TNF-α-inflamed cremaster muscle venules. Studies with DREAM bone marrow chimeras revealed that both hematopoietic and EC DREAM are important for neutrophil recruitment. We found that neutrophils lacking DREAM exhibit reduced αMβ2 surface expression and decrease fibrinogen binding following stimulation with TNF-α, but not fMLF, implying the role for neutrophil DREAM in regulating β2 integrin function through a specific signaling pathway. Since recent studies demonstrated the important role of endothelial cell DREAM in NF-κB signaling, we further examined whether neutrophil DREAM regulates NF-κB signaling. Indeed, the protein expression of A20 (an inhibitor of NF-κB signaling) and p65 (a key subunit of the NF-κB complex) was significantly up- and down-regulated, respectively, in DREAM-deficient neutrophils, compared to WT neutrophils. Moreover, DREAM deletion impaired the phosphorylation of IKKa/β following TNF-a-stimulation, suggesting the role of neutrophil DREAM in NF-κB signaling. Consistently, we found that the transcription of the NF-κB target genes, such as IL-1β, TNF-α, and IL-6, was inhibited by DREAM deletion. Taken together, our results provide evidence that neutrophil DREAM is a novel regulator for β2 integrin function through NF-κB signaling and could be a therapeutic target for treatment of inflammatory disease. DisclosuresNo relevant conflicts of interest to declare.