Gremlin-1 is an inhibitor of macrophage migration inhibitory factor and attenuates atherosclerotic plaque growth in ApoE-/- mice

Research output: Journal contributionsJournal articlesResearchpeer-review

Authors

  • Iris Müller
  • Tanja Schönberger
  • Martina Schneider
  • Oliver Borst
  • Melanie Ziegler
  • Peter Seizer
  • Christoph Leder
  • Karin Müller
  • Michael Lang
  • Florian Appenzeller
  • Oleg Lunov
  • Berthold Büchele
  • Manuela Fahrleitner
  • Marcus Olbrich
  • Harald Langer
  • Tobias Geisler
  • Florian Lang
  • Madhumita Chatterjee
  • Jan Freark de Boer
  • Uwe J Tietge
  • And 3 others
  • Jürgen Bernhagen
  • Thomas Simmet
  • Meinrad Gawaz

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 (K D = 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.

Original languageEnglish
JournalThe Journal of Biological Chemistry
Volume288
Issue number44
Pages (from-to)31635-31645
Number of pages11
DOIs
Publication statusPublished - 01.11.2013

Bibliographical note

DFG Funding: MU 2928/2-1

DOI