Peter Stachon1, Alexander Peikert1, Nathaly Anto Michel1, Sonja Hergeth1, Timoteo Marchini1, Dennis Wolf1, Bianca Dufner1, Natalie Hoppe1, Cemil Korcan Ayata1, Melanie Grimm1, Sanja Cicko1, Lisa Schulte1, Jochen Reinöhl1, Constantin von zur Muhlen1, Christoph Bode1, Marco Idzko1, Andreas Zirlik2. 1. From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.). 2. From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.). andreas.zirlik@universitaets-herzzentrum.de.
Abstract
OBJECTIVE: Nucleotides such as ATP, ADP, UTP, and UDP serve as proinflammatory danger signals via purinergic receptors on their release to the extracellular space by activated or dying cells. UDP binds to the purinergic receptor Y6 (P2Y6) and propagates vascular inflammation by inducing the expression of chemokines such as monocyte chemoattractant protein 1, interleukin-8, or its mouse homologsCCL1 (chemokine [C-C motif] ligand 1)/keratinocyte chemokine, CXCL2 (chemokine [C-X-C motif] ligand 2)/macrophage inflammatory protein 2, and CXCL5 (chemokine [C-X-C motif] ligand 5)/LIX, and adhesion molecules such as vascular cell adhesion molecule 1 and intercellular cell adhesion molecule 1. Thus, P2Y6 contributes to leukocyte recruitment and inflammation in conditions such as allergic asthma or sepsis. Because atherosclerosis is a chronic inflammatory disease driven by leukocyte recruitment to the vessel wall, we hypothesized a role of P2Y6 in atherogenesis. APPROACH AND RESULTS: Intraperitoneal stimulation of wild-type mice with UDP induced rolling and adhesion of leukocytes to the vessel wall as assessed by intravital microscopy. This effect was not present in P2Y6-deficient mice. Atherosclerotic aortas of low-density lipoprotein receptor-deficient mice consuming high-cholesterol diet for 16 weeks expressed significantly more transcripts and protein of P2Y6 than respective controls. Finally, P2Y6 (-/-)/low-density lipoprotein receptor-deficient mice consuming high-cholesterol diet for 16 weeks developed significantly smaller atherosclerotic lesions compared with P2Y6 (+/+)/low-density lipoprotein receptor-deficient mice. Bone marrow transplantation identified a crucial role of P2Y6 on vascular resident cells, most likely endothelial cells, on leukocyte recruitment and atherogenesis. Atherosclerotic lesions of P2Y6-deficient mice contained fewer macrophages and fewer lipids as determined by immunohistochemistry. Mechanistically, RNA expression of vascular cell adhesion molecule 1 and interleukin-6 was decreased in these lesions and P2Y6-deficient macrophages took up less modified low-density lipoprotein cholesterol. CONCLUSIONS: We show for the first time that P2Y6 deficiency limits atherosclerosis and plaque inflammation in mice.
OBJECTIVE: Nucleotides such as ATP, ADP, UTP, and UDP serve as proinflammatory danger signals via purinergic receptors on their release to the extracellular space by activated or dying cells. UDP binds to the purinergic receptor Y6 (P2Y6) and propagates vascular inflammation by inducing the expression of chemokines such as monocyte chemoattractant protein 1, interleukin-8, or its mouse homologsCCL1 (chemokine [C-C motif] ligand 1)/keratinocyte chemokine, CXCL2 (chemokine [C-X-C motif] ligand 2)/macrophage inflammatory protein 2, and CXCL5 (chemokine [C-X-C motif] ligand 5)/LIX, and adhesion molecules such as vascular cell adhesion molecule 1 and intercellular cell adhesion molecule 1. Thus, P2Y6 contributes to leukocyte recruitment and inflammation in conditions such as allergic asthma or sepsis. Because atherosclerosis is a chronic inflammatory disease driven by leukocyte recruitment to the vessel wall, we hypothesized a role of P2Y6 in atherogenesis. APPROACH AND RESULTS: Intraperitoneal stimulation of wild-type mice with UDP induced rolling and adhesion of leukocytes to the vessel wall as assessed by intravital microscopy. This effect was not present in P2Y6-deficient mice. Atherosclerotic aortas of low-density lipoprotein receptor-deficient mice consuming high-cholesterol diet for 16 weeks expressed significantly more transcripts and protein of P2Y6 than respective controls. Finally, P2Y6 (-/-)/low-density lipoprotein receptor-deficient mice consuming high-cholesterol diet for 16 weeks developed significantly smaller atherosclerotic lesions compared with P2Y6 (+/+)/low-density lipoprotein receptor-deficient mice. Bone marrow transplantation identified a crucial role of P2Y6 on vascular resident cells, most likely endothelial cells, on leukocyte recruitment and atherogenesis. Atherosclerotic lesions of P2Y6-deficientmice contained fewer macrophages and fewer lipids as determined by immunohistochemistry. Mechanistically, RNA expression of vascular cell adhesion molecule 1 and interleukin-6 was decreased in these lesions and P2Y6-deficient macrophages took up less modified low-density lipoprotein cholesterol. CONCLUSIONS: We show for the first time that P2Y6deficiency limits atherosclerosis and plaque inflammation in mice.
Authors: Timoteo Marchini; Dennis Wolf; Nathaly Anto Michel; Maximilian Mauler; Bianca Dufner; Natalie Hoppe; Jessica Beckert; Markus Jäckel; Natalia Magnani; Daniel Duerschmied; Deborah Tasat; Silvia Alvarez; Jochen Reinöhl; Constantin von Zur Muhlen; Marco Idzko; Christoph Bode; Ingo Hilgendorf; Pablo Evelson; Andreas Zirlik Journal: Basic Res Cardiol Date: 2016-05-30 Impact factor: 17.165
Authors: Tobias Müller; Susanne Fay; Rodolfo Paula Vieira; Harry Karmouty-Quintana; Sanja Cicko; Cemil Korcan Ayata; Gernot Zissel; Torsten Goldmann; Giuseppe Lungarella; Davide Ferrari; Francesco Di Virgilio; Bernard Robaye; Jean-Marie Boeynaems; Eduardo R Lazarowski; Michael R Blackburn; Marco Idzko Journal: Front Immunol Date: 2017-08-22 Impact factor: 7.561