Endothelial BMP4 Promotes Leukocyte Rolling and Adhesion and Is Elevated in Patients After Survived Out-of-Hospital Card
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ORIGINAL ARTICLE
Endothelial BMP4 Promotes Leukocyte Rolling and Adhesion and Is Elevated in Patients After Survived Out-of-Hospital Cardiac Arrest Linus Arnold,1 Miki Weberbauer,1 Marius Herkel,1 Katrin Fink,2 Hans-Jörg Busch,2 Philipp Diehl,1 Sebastian Grundmann,1 Christoph Bode,1 Albrecht Elsässer,3 Martin Moser,1 and Thomas Helbing 1,3,4
Leukocyte recruitment is a fundamental step in the inflammatory response during ischemia/reperfusion injury (IRI). Rolling and adhesion of leukocytes to activated endothelium promote tissue inflammation after IRI and require presentation of adhesion molecules E-selectin and ICAM-1 on the endothelial surface. Bone morphogenetic protein (BMP) 4 is a prominent member of the BMP family expressed and secreted by endothelial cells. BMP4 derived from endothelial cells has important functions in vascular disease but its influence on the leukocyte adhesion cascade during inflammation is incompletely understood. In the present study, we challenged mice with an inducible endothelial-specific BMP4 deletion (referred to as EC-BMP4−/− mice) and their control littermates (EC-BMP4+/+) with thioglycollate i.p. and assessed extravasation of different leukocyte subsets during peritonitis. Peritoneal lavages were performed and peritoneal cells were counted. Total cell count in lavages of EC-BMP4−/− mice was markedly reduced compared with lavages of EC-BMP4+/+ mice. FACS analyses of thioglycollate-elicited peritoneal cells revealed that diverse leukocyte subsets were reduced in EC-BMP4−/− mice. Intravital microscopy of cremaster venules demonstrated that rolling and adhesion of leukocytes were significantly diminished in ECBMP4−/− mice in comparison with control mice in response to TNFα. These observations indicate that endothelial BMP4 is essential for rolling, adhesion, and extravasation of leukocytes in vivo. To understand the underlying mechanisms, levels of endothelial adhesion molecules E-selectin and ICAM-1 were quantified in EC-BMP4−/− and ECBMP4+/+ mice by quantitative PCR and Western blotting. Interestingly, ICAM-1 and Eselectin expressions were reduced in the hearts of EC-BMP4−/− mice. Next we confirmed proinflammatory properties of BMP4 in a gain of function experiments and found that administration of recombinant BMP4 in male C57BL/6 mice increased leukocyte rolling and Abstract—
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10753-020-01307-9) contains supplementary material, which is available to authorized users.
3
Department of Cardiology, Heart Center Oldenburg, Carl von Ossietzky University, Oldenburg, Germany
4
To whom correspondence should be addressed at Department of Cardiology, Heart Center Oldenburg, Carl von Ossietzky University, Oldenburg, Germany. E-mail: [email protected]
1
Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany 2 Department of Emergency Medicine, Faculty of Medicine, University of Freiburg, Freiburg,
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