Giulia Chinetti-Gbaguidi1, Mehdi Daoudi1, Mickael Rosa1, Manjula Vinod1, Loïc Louvet1, Corinne Copin1, Mélanie Fanchon1, Jonathan Vanhoutte1, Bruno Derudas1, Loic Belloy1, Stephan Haulon1, Christophe Zawadzki1, Sophie Susen1, Ziad A Massy1, Jérôme Eeckhoute1, Bart Staels2. 1. From the Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011, EGID, Lille, France (G.C.-G., M.D., M.R., M.V., C.C., M.F., J.V., B.D., L.B., C.Z., S.S., J.E., B.S.); University of Côte d'Azur, CHU, Inserm, CNRS, IRCAN, Nice, France (G.C.-G.); Inserm U1088, University of Picardie Jules Verne, and Amiens University Hospital, Amiens, France (L.L.); CHU Lille, Lille, France (S.H.); Division of Nephrology, Ambroise Paré University Hospital, AP-HP, Boulogne-Billancourt (Z.A.M.); and INSERM U1018, Team 5, CESP, UVSQ, Paris-Saclay University, Villejuif/Paris, France (Z.A.M.). 2. From the Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011, EGID, Lille, France (G.C.-G., M.D., M.R., M.V., C.C., M.F., J.V., B.D., L.B., C.Z., S.S., J.E., B.S.); University of Côte d'Azur, CHU, Inserm, CNRS, IRCAN, Nice, France (G.C.-G.); Inserm U1088, University of Picardie Jules Verne, and Amiens University Hospital, Amiens, France (L.L.); CHU Lille, Lille, France (S.H.); Division of Nephrology, Ambroise Paré University Hospital, AP-HP, Boulogne-Billancourt (Z.A.M.); and INSERM U1018, Team 5, CESP, UVSQ, Paris-Saclay University, Villejuif/Paris, France (Z.A.M.). bart.staels@pasteur-lille.fr.
Abstract
RATIONALE: Vascular calcification is a process similar to bone formation leading to an inappropriate deposition of calcium phosphate minerals in advanced atherosclerotic plaques. Monocyte-derived macrophages, located in atherosclerotic lesions and presenting heterogeneous phenotypes, from classical proinflammatory M1 to alternative anti-inflammatory M2 macrophages, could potentially display osteoclast-like functions. OBJECTIVE: To characterize the phenotype of macrophages located in areas surrounding the calcium deposits in human atherosclerotic plaques. METHODS AND RESULTS: Macrophages near calcium deposits display an alternative phenotype being both CD68 and mannose receptor-positive, expressing carbonic anhydrase type II, but relatively low levels of cathepsin K. In vitro interleukin-4-polarization of human primary monocytes into macrophages results in lower expression and activity of cathepsin K compared with resting unpolarized macrophages. Moreover, interleukin-4 polarization lowers expression levels of the osteoclast transcriptional activator nuclear factor of activated T cells type c-1, associated with increased gene promoter levels of the transcriptional repression mark H3K27me3 (histone 3 lysine 27 trimethylation). Despite higher expression of the receptor activator of nuclear factor κB receptor, receptor activator of nuclear factor κB ligand/macrophage colony-stimulating factor induction of nuclear factor of activated T cells type c-1 and cathepsin K expression is defective in these macrophages because of reduced Erk/c-fos-mediated downstream signaling resulting in impaired bone resorption capacity. CONCLUSIONS: These results indicate that macrophages surrounding calcium deposits in human atherosclerotic plaques are phenotypically defective being unable to resorb calcification.
RATIONALE: Vascular calcification is a process similar to bone formation leading to an inappropriate deposition of calcium phosphate minerals in advanced atherosclerotic plaques. Monocyte-derived macrophages, located in atherosclerotic lesions and presenting heterogeneous phenotypes, from classical proinflammatory M1 to alternative anti-inflammatory M2 macrophages, could potentially display osteoclast-like functions. OBJECTIVE: To characterize the phenotype of macrophages located in areas surrounding the calcium deposits in humanatherosclerotic plaques. METHODS AND RESULTS: Macrophages near calcium deposits display an alternative phenotype being both CD68 and mannose receptor-positive, expressing carbonic anhydrase type II, but relatively low levels of cathepsin K. In vitro interleukin-4-polarization of human primary monocytes into macrophages results in lower expression and activity of cathepsin K compared with resting unpolarized macrophages. Moreover, interleukin-4 polarization lowers expression levels of the osteoclast transcriptional activator nuclear factor of activated T cells type c-1, associated with increased gene promoter levels of the transcriptional repression mark H3K27me3 (histone 3 lysine 27 trimethylation). Despite higher expression of the receptor activator of nuclear factor κB receptor, receptor activator of nuclear factor κB ligand/macrophage colony-stimulating factor induction of nuclear factor of activated T cells type c-1 and cathepsin K expression is defective in these macrophages because of reduced Erk/c-fos-mediated downstream signaling resulting in impaired bone resorption capacity. CONCLUSIONS: These results indicate that macrophages surrounding calcium deposits in humanatherosclerotic plaques are phenotypically defective being unable to resorb calcification.
Authors: Michael Wierer; Matthias Prestel; Herbert B Schiller; Guangyao Yan; Christoph Schaab; Sepiede Azghandi; Julia Werner; Thorsten Kessler; Rainer Malik; Marta Murgia; Zouhair Aherrahrou; Heribert Schunkert; Martin Dichgans; Matthias Mann Journal: Mol Cell Proteomics Date: 2017-12-04 Impact factor: 5.911
Authors: Till Seime; Asim Cengiz Akbulut; Moritz Lindquist Liljeqvist; Antti Siika; Hong Jin; Greg Winski; Rick H van Gorp; Eva Karlöf; Mariette Lengquist; Andrew J Buckler; Malin Kronqvist; Olivia J Waring; Jan H N Lindeman; Erik A L Biessen; Lars Maegdefessel; Anton Razuvaev; Leon J Schurgers; Ulf Hedin; Ljubica Matic Journal: Cells Date: 2021-05-21 Impact factor: 6.600