title: Gremlin-1 is an inhibitor of macrophage migration inhibitory factor and attenuates atherosclerotic plaque growth in ApoE-/- Mice.
abstract: Monocyte infiltration and macrophage formation are pivotal steps in atherosclerosis and plaque vulnerability. Gremlin-1/Drm is crucial in embryo-/organogenesis and has been shown to be expressed in the adult organism at sites of arterial injury and to inhibit monocyte migration. The purpose of the present study was to evaluate and characterize the role of Gremlin-1 in atherosclerosis. Here we report that Gremlin-1 is highly expressed primarily by monocytes/macrophages in aortic atherosclerotic lesions of ApoE(-/-) mice and is secreted from activated monocytes and during macrophage development in vitro. Gremlin-1 reduces macrophage formation by inhibiting macrophage migration inhibitory factor (MIF), a cytokine critically involved in atherosclerotic plaque progression and vulnerability. Gremlin-1 binds with high affinity to MIF (KD = 54 nm), as evidenced by surface plasmon resonance analysis and co-immunoprecipitation, and reduces MIF-induced release of TNF-α from macrophages. Treatment of ApoE(-/-) mice with a dimeric recombinant fusion protein, mGremlin1-Fc, but not with equimolar control Fc or inactivated mGremlin1-Fc, reduced TNF-α expression, the content of monocytes/macrophages of atherosclerotic lesions, and attenuated atheroprogression. The present data disclose that Gremlin-1 is an endogenous antagonist of MIF and define a role for Gremlin-1/MIF interaction in atherosclerosis.
authors.affiliation: From the Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls Universität, 72076 Tübingen, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Müller
authors.forename: Tanja
authors.initials: T
authors.lastname: Schönberger
authors.forename: Martina
authors.initials: M
authors.lastname: Schneider
authors.forename: Oliver
authors.initials: O
authors.lastname: Borst
authors.forename: Melanie
authors.initials: M
authors.lastname: Ziegler
authors.forename: Peter
authors.initials: P
authors.lastname: Seizer
authors.forename: Christoph
authors.initials: C
authors.lastname: Leder
authors.forename: Karin
authors.initials: K
authors.lastname: Müller
authors.forename: Michael
authors.initials: M
authors.lastname: Lang
authors.forename: Florian
authors.initials: F
authors.lastname: Appenzeller
authors.forename: Oleg
authors.initials: O
authors.lastname: Lunov
authors.forename: Berthold
authors.initials: B
authors.lastname: Büchele
authors.forename: Manuela
authors.initials: M
authors.lastname: Fahrleitner
authors.forename: Marcus
authors.initials: M
authors.lastname: Olbrich
authors.forename: Harald
authors.initials: H
authors.lastname: Langer
authors.forename: Tobias
authors.initials: T
authors.lastname: Geisler
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Madhumita
authors.initials: M
authors.lastname: Chatterjee
authors.forename: Jan Freark
authors.initials: JF
authors.lastname: de Boer
authors.forename: Uwe J F
authors.initials: UJ
authors.lastname: Tietge
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bernhagen
authors.forename: Thomas
authors.initials: T
authors.lastname: Simmet
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
mesh_terms: D000818:Animals; D001057:Apolipoproteins E; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis / Q000235:genetics; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D016207:Cytokines
chemical_list: D001057:Apolipoproteins E; D036341:Intercellular Signaling Peptides and Proteins; D019746:Intramolecular Oxidoreductases; D008263:Macrophage Migration-Inhibitory Factors; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C486399:GREM1 protein, human; C515598:MIF protein, human; C076231:Mif protein, mouse; C113178:Grem1 protein, mouse; D016207:Cytokines
keywords: Atherosclerosis; Chemokines; Inflammation; Monocytes; Vascular Biology