Spatiotemporal expression dynamics of selectins govern the sequential extravasation of neutrophils and monocytes in the acute inflammatory response.
OBJECTIVE
Leukocyte recruitment to the site of inflammation is a key event in a variety of cardiovascular pathologies. Infiltrating neutrophils constitute the first line of defense that precedes a second wave of emigrating monocytes reinforcing the inflammatory reaction. The mechanisms initiating this sequential process remained largely obscure.


RESULTS
Using advanced in vivo microscopy and in vitro/ex vivo techniques, we identified individual spatiotemporal expression patterns of selectins and their principal interaction partners on neutrophils, resident/inflammatory monocytes, and endothelial cells. Coordinating the intraluminal trafficking of neutrophils and inflammatory monocytes to common sites of extravasation, selectins assign different sites to these immune cells for their initial interactions with the microvascular endothelium. Whereas constitutively expressed leukocyte L-selectin/CD62L and endothelial P-selectin/CD62P together with CD44 and P-selectin glycoprotein ligand-1/CD162 initiate the emigration of neutrophils, de novo synthesis of endothelial E-selectin/CD62E launches the delayed secondary recruitment of inflammatory monocytes. In this context, P-selectin/CD62P and L-selectin/CD62L together with P-selectin glycoprotein ligand-1/CD162 and CD44 were found to regulate the flux of rolling neutrophils and inflammatory monocytes, whereas E-selectin/CD62E selectively adjusts the rolling velocity of inflammatory monocytes. Moreover, selectins and their interaction partners P-selectin glycoprotein ligand-1/CD162 and CD44 differentially control the intraluminal crawling behavior of neutrophils and inflammatory monocytes collectively enabling the sequential extravasation of these immune cells to inflamed tissue.


CONCLUSIONS
Our findings provide novel insights into the mechanisms initiating the sequential infiltration of the perivascular tissue by neutrophils and monocytes in the acute inflammatory response and might thereby contribute to the development of targeted therapeutic strategies for prevention and treatment of cardiovascular diseases.
From the Department of Otorhinolaryngology, Head and Neck Surgery (G.Z., C.A.R.), Department of Radiation Oncology (K.L.), Walter Brendel Centre of Experimental Medicine (G.Z., B.U., M.E.T.H., A.R.M.K., M.R., F.K., C.A.R.), Klinikum der Universität München, Munich, Germany.
Gabriele
G
Zuchtriegel
From the Department of Otorhinolaryngology, Head and Neck Surgery (G.Z., C.A.R.), Department of Radiation Oncology (K.L.), Walter Brendel Centre of Experimental Medicine (G.Z., B.U., M.E.T.H., A.R.M.K., M.R., F.K., C.A.R.), Klinikum der Universität München, Munich, Germany.
Bernd
B
Uhl
From the Department of Otorhinolaryngology, Head and Neck Surgery (G.Z., C.A.R.), Department of Radiation Oncology (K.L.), Walter Brendel Centre of Experimental Medicine (G.Z., B.U., M.E.T.H., A.R.M.K., M.R., F.K., C.A.R.), Klinikum der Universität München, Munich, Germany.
Maximilian E T
ME
Hessenauer
From the Department of Otorhinolaryngology, Head and Neck Surgery (G.Z., C.A.R.), Department of Radiation Oncology (K.L.), Walter Brendel Centre of Experimental Medicine (G.Z., B.U., M.E.T.H., A.R.M.K., M.R., F.K., C.A.R.), Klinikum der Universität München, Munich, Germany.
Angela R M
AR
Kurz
From the Department of Otorhinolaryngology, Head and Neck Surgery (G.Z., C.A.R.), Department of Radiation Oncology (K.L.), Walter Brendel Centre of Experimental Medicine (G.Z., B.U., M.E.T.H., A.R.M.K., M.R., F.K., C.A.R.), Klinikum der Universität München, Munich, Germany.
Markus
M
Rehberg
From the Department of Otorhinolaryngology, Head and Neck Surgery (G.Z., C.A.R.), Department of Radiation Oncology (K.L.), Walter Brendel Centre of Experimental Medicine (G.Z., B.U., M.E.T.H., A.R.M.K., M.R., F.K., C.A.R.), Klinikum der Universität München, Munich, Germany.
Kirsten
K
Lauber
From the Department of Otorhinolaryngology, Head and Neck Surgery (G.Z., C.A.R.), Department of Radiation Oncology (K.L.), Walter Brendel Centre of Experimental Medicine (G.Z., B.U., M.E.T.H., A.R.M.K., M.R., F.K., C.A.R.), Klinikum der Universität München, Munich, Germany.
Fritz
F
Krombach
From the Department of Otorhinolaryngology, Head and Neck Surgery (G.Z., C.A.R.), Department of Radiation Oncology (K.L.), Walter Brendel Centre of Experimental Medicine (G.Z., B.U., M.E.T.H., A.R.M.K., M.R., F.K., C.A.R.), Klinikum der Universität München, Munich, Germany. christoph.reichel@med.uni-muenchen.de.
Christoph A
CA
Reichel
D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D006439:Hemodynamics; D018960:Hyaluronan Receptors / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism*; D036904:Leukocyte Rolling; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008833:Microcirculation; D055806:Microvessels / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D019007:P-Selectin / Q000378:metabolism*; D010538:Peritonitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D057705:Transendothelial and Transepithelial Migration
D000073883:CX3C Chemokine Receptor 1; C476399:Cd44 protein, mouse; C471885:Cx3cr1 protein, mouse; D016207:Cytokines; D018960:Hyaluronan Receptors; D018836:Inflammation Mediators; D008024:Ligands; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D019707:Receptors, Chemokine; D019041:L-Selectin
endothelium; immune system; inflammation; leukocytes; microcirculation