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Ligation of the adhesion-GPCR EMR2 regulates human neutrophil function

Simon Yona^*, Hsi-Hsien Lin, Pietro Dri, John Q. Davies^*, Richard P. G. Hayhoe, Sion M. Lewis^||, Sigrid E. M. Heinsbroek^*, K. Alun Brown^||, Mauro Perretti, Jörg Hamann^¶, David F. Treacher^||, Siamon Gordon^*,1 and Martin Stacey^*,1

^* Sir William Dunn School of Pathology, Oxford University, Oxford, UK;

Department of Microbiology and Immunology, Chang Gung University, Gueishan, Taoyuan, Taiwan, Republic of China;

Department of Physiology and Pathology, University of Trieste, Trieste, Italy;

William Harvey Research Institute, University of London, London, UK;

^|| St. Thomas’ Hospital, Kings College, London, UK; and

^¶ Department of Experimental Immunology, University of Amsterdam, Amsterdam, Holland

¹Correspondence: Sir William Dunn School of Pathology, Oxford University, Oxford, OX1 3RE, UK. E-mail: M.S., martin.stacey{at}path.ox.ac.uk; S.G., siamon.gordon{at}path.ox.ac.uk

At present, 150 different members of the adhesion-G protein-coupled receptor (GPCR) family have been identified in metazoans. Surprisingly, very little is known about their function, although they all possess large extracellular domains coupled to a seven-transmembrane domain, suggesting a potential role in cell adhesion and signaling. Here, we demonstrate how the human-restricted adhesion-GPCR, EMR2 (epidermal growth factor-like module-containing mucin-like hormone receptor), regulates neutrophil responses by potentiating the effects of a number of proinflammatory mediators and show that the transmembrane region is critical for adhesion-GPCR function. Using an anti-EMR2 antibody, ligation of EMR2 increases neutrophil adhesion and migration, and augments superoxide production and proteolytic enzyme degranulation. On neutrophil activation, EMR2 is rapidly translocated to membrane ruffles and the leading edge of the cell. Further supporting the role in neutrophil activation, EMR2 expression on circulating neutrophils is significantly increased in patients with systemic inflammation. These data illustrate a definitive function for a human adhesion-GPCR within the innate immune system and suggest an important role in potentiating the inflammatory response. Ligation of the adhesion-GPCR EMR2 regulates human neutrophil function.—Yona, S., Lin, H.-H., Dri, P., Davies, J. Q., Hayhoe, R. P. G., Lewis, S. M., Heinsbroek, S. E. M., Brown, K. A., Perretti, M., Hamann, J., Treacher, D. F., Gordon, S., Stacey, M. Ligation of the adhesion-GPCR EMR2 regulates human neutrophil function.

Key Words: inflammation • migration • sepsis

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