Rolle von Alarminen aus neutrophilen Granulozyten in der Atherosklerose
Final Report Abstract
While atherosclerosis is generally considered a monocyte-driven inflammation of the vessel wall, we here asked what the specific contribution of neutrophils, the most abundant circulating white blood cell subset in humans, towards atherosclerosis is. Using mouse models of neutropenia and neutrophilia we could evidence a direct relationship between circulating neutrophil counts and atherosclerosis lesion formation suggesting a causative role of 47mmune47phils in atherosclerosis. Mechanistically, we were able to identify CCR1, CCR2, CCR5, and CXCR2 as receptors guiding neutrophil recruitment into atherosclerotic lesions. The proatherogenic effect of neutrophils was found to rest upon their ability to release preformed chemotactic granule proteins. When interacting with host-DNA these granule proteins are recognized by plasmacytoid dendritic cells and hence unleash an interferon-alpha triggered inflammatory response. In addition, granule proteins immobilized on endothelial cells directly induce adhesion and recruitment of classical monocytes by strengthening integrin activation.
Publications
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Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis. Circulation. 2010; 122:1837-45
Drechsler M, Megens RT, van Zandvoort M, Weber C, Soehnlein O
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Neutrophil-derived cathelicidin protects from neointimal hyperplasia. Sci Transl Med. 2011; 3:103ra98
Soehnlein O, Wantha S, Simsekyilmaz S, Döring Y, Megens RT, Mause SF, Drechsler M, Smeets R, Weinandy S, Schreiber F, Gries T, Jockenhoevel S, Möller M, Vijayan S, van Zandvoort MA, Agerberth B, Pham CT, Gallo RL, Hackeng TM, Liehn EA, Zernecke A, Klee D, Weber C
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Auto-antigenic protein-DNA complexes stimulate plasmacytoid dendritic cells to promote atherosclerosis. Circulation. 2012; 125:1673-83
Döring Y, Manthey HD, Drechsler M, Lievens D, Megens RT, Soehnlein O, Busch M, Manca M, Koenen RR, Pelisek J, Daemen MJ, Lutgens E, Zenke M, Binder CJ, Weber C, Zernecke A
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Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury. Am J Respir Crit Care Med. 2012; 185:628-36
Grommes J, Alard JE, Drechsler M, Wantha S, Mörgelin M, Kuebler WM, Jacobs M, von Hundelshausen P, Markart P, Wygrecka M, Preissner KT, Hackeng TM, Koenen RR, Weber C, Soehnlein O
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Hematopoietic interferon regulatory factor 8-deficiency accelerates atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 2012a; 32:1613-23
Döring Y, Soehnlein O, Drechsler M, Shagdarsuren E, Chaudhari SM, Meiler S, Hartwig H, Hristov M, Koenen RR, Hieronymus T, Zenke M, Weber C, Zernecke A
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Lack of neutrophil-derived CRAMP reduces atherosclerosis in mice. Circ Res. 2012; 110:1052-6
Döring Y, Drechsler M, Wantha S, Kemmerich K, Lievens D, Vijayan S, Gallo RL, Weber C, Soehnlein O
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Presence of luminal neutrophil extracellular traps in atherosclerosis. Thromb Haemost. 2012; 107:597-8
Megens RT, Vijayan S, Lievens D, Döring Y, van Zandvoort MA, Grommes J, Weber C, Soehnlein O
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Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes. EMBO Mol Med. 2013; 5:471-81
Soehnlein O, Drechsler M, Döring Y, Lievens D, Hartwig H, Kemmerich K, Ortega-Gómez A, Mandl M, Vijayan S, Projahn D, Garlichs CD, Koenen RR, Hristov M, Lutgens E, Zernecke A, Weber C
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Neutrophil-derived cathelicidin promotes adhesion of classical monocytes. Circ Res. 2013; 112:792-801
Wantha S, Alard JE, Megens RT, van der Does AM, Döring Y, Drechsler M, Pham CT, Wang MW, Wang JM, Gallo RL, von Hundelshausen P, Lindbom L, Hackeng T, Weber C, Soehnlein O
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Deficiency of the sialyltransferase St3Gal4 reduces Ccl5-mediated myeloid cell recruitment and arrest: short communication. Circ Res. 2014; 114:976-81
Döring Y, Noels H, Mandl M, Kramp B, Neideck C, Lievens D, Drechsler M, Megens RT, Tilstam PV, Langer M, Hartwig H, Theelen W, Marth JD, Sperandio M, Soehnlein O, Weber C
