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-α but not MIP-2 or fMLP. We observe that neutrophil DREAM represses expression of A20, a negative regulator of NF-κB activity, and enhances expression of pro-inflammatory molecules and phosphorylation of IκB kinase (IKK) after TNF-α stimulation. Studies using genetic and pharmacologic approaches reveal that DREAM deficiency and IKKβ inhibition significantly diminish the ligand-binding activity of β2 integrins in TNF-α–stimulated neutrophils or neutrophil-like HL-60 cells. Neutrophil DREAM promotes degranulation through IKKβ-mediated SNAP-23 phosphorylation. Using sickle cell disease mice lacking DREAM, we show that hematopoietic DREAM promotes vaso-occlusive events in microvessels following TNF-α challenge. Our study provides evidence that targeting DREAM might be a novel therapeutic strategy to reduce excessive neutrophil recruitment in inflammatory diseases.
Neutrophil DREAM promotes neutrophil recruitment in vascular inflammation
Disclosures: The authors declare no competing interests exist.
A. Barazia’s present address is Intelligent Imaging Innovations, Denver, CO.
B.K. Lee’s present address is Department of Biomedical Sciences, Cancer Research Center, University at Albany–State University of New York, Rensselaer, NY.
S.Y. Jeong’s present address is Division of Pharmaceutical Policy, Pharmaceutical Safety Bureau, Ministry of Food and Drug Safety, Cheongju-si, South Korea.
- Award Id(s): ,HL125838,HL146559,HL153047,HL130028,HL148280,HL140837,HD101512,GM112722BX003415
- Award Id(s): 18CDA34110402
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Jing Li, Tripti Kumari, Andrew Barazia, Vishwanath Jha, Si-Yeon Jeong, Amber Olson, Mijeong Kim, Bum-Kyu Lee, Vijayprakash Manickam, Zhimin Song, Regina Clemens, Babak Razani, Jonghwan Kim, Mary C. Dinauer, Jaehyung Cho; Neutrophil DREAM promotes neutrophil recruitment in vascular inflammation. J Exp Med 3 January 2022; 219 (1): e20211083. doi: https://doi.org/10.1084/jem.20211083
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