title: High expression of C5L2 correlates with high proinflammatory cytokine expression in advanced human atherosclerotic plaques.
abstract: The complement anaphylatoxin C5a functions through its two receptors, C5aR (CD88) and C5a receptor-like 2 (C5L2). Their role in atherosclerosis is incompletely understood. We, therefore, analyzed C5aR and probed the yet unknown expression and function of C5L2 in human atherogenesis. Human atherosclerotic plaques obtained by endarterectomy were staged and analyzed for C5L2 and C5aR by IHC and quantitative real-time PCR. C5L2-expressing cells in plaques were mostly macrophages, less neutrophils and endothelial cells, as determined by double immunostaining. Although early influx of C5aR(+) cells was detected, C5L2 levels increased with lesion complexity and colocalized with C5aR and oxidized low-density lipoprotein. Gene expression of C5L2 and C5aR showed similar trends, such as the receptor-expressing cells. The expression of C5L2 in advanced lesions correlated with increased levels of IL-1β and tumor necrosis factor-α in plaques. Furthermore, in vitro experiments in macrophages from wild-type and C5l2- and C5ar-deficient mice corroborated the contributing role of C5l2 in oxidized low-density lipoprotein-pretreated C5a-induced cytokine expression, as measured by enzyme-linked immunosorbent assay. Finally, C5l2- and C5ar-deficient peripheral blood mononuclear cells showed less arrest on tumor necrosis factor-α-stimulated mouse endothelial cells in vitro when compared with wild-type controls. Taken together, prominent C5L2 expression in advanced atherosclerotic stages directly correlates with high levels of proinflammatory cytokines. This might indicate a proinflammatory role of C5L2 in atherosclerosis that needs to be pursued in the future by applying in vivo mouse models.
authors.affiliation: Institute for Molecular Cardiovascular Research, University Hospital, Aachen, Germany; Institute for Pharmacology and Clinical Pharmacology, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: Santosh
authors.initials: S
authors.lastname: Vijayan
authors.affiliation: Institute for Molecular Cardiovascular Research, University Hospital, Aachen, Germany; Institute of Biochemistry and Molecular Cell Biology, University Hospital, Aachen, Germany.
authors.forename: Yaw
authors.initials: Y
authors.lastname: Asare
authors.affiliation: European Vascular Centre Aachen-Maastricht, University Hospital, Aachen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Grommes
authors.affiliation: Institute for Molecular Cardiovascular Research, University Hospital, Aachen, Germany; Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Soehnlein
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany; Department of Medical Biochemistry, Amsterdam Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Lutgens
authors.affiliation: Department of Nephrology, Health Sciences University of Mongolia, Ulaanbaatar, Mongolia.
authors.forename: Gansuvd
authors.initials: G
authors.lastname: Shagdarsuren
authors.affiliation: Department of Nephrology, Health Sciences University of Mongolia, Ulaanbaatar, Mongolia.
authors.forename: Ariunaa
authors.initials: A
authors.lastname: Togtokh
authors.affiliation: European Vascular Centre Aachen-Maastricht, University Hospital, Aachen, Germany; European Vascular Center Aachen-Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jacobs
authors.affiliation: Institute for Pharmacology and Clinical Pharmacology, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: Jens W
authors.initials: JW
authors.lastname: Fischer
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology, University Hospital, Aachen, Germany; August-Lenz-Stiftung at Ludwig-Maximilians-University Hospital Munich, Munich, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bernhagen
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany; Department of Medical Biochemistry, Amsterdam Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: Institute for Molecular Cardiovascular Research, University Hospital, Aachen, Germany; Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schober
authors.affiliation: Institute for Molecular Cardiovascular Research, University Hospital, Aachen, Germany. Electronic address: eguenther@ukaachen.de.
authors.forename: Erdenechimeg
authors.initials: E
authors.lastname: Shagdarsuren
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D044087:Receptor, Anaphylatoxin C5a / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C488033:C5AR1 protein, human; C417003:C5aR2 protein, human; D016207:Cytokines; D053583:Interleukin-1beta; D008077:Lipoproteins, LDL; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein