Article abstract
Nature Medicine 13, 587 - 596 (2007)
Published online: 15 April 2007 | doi:10.1038/nm1567
MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment
Jürgen Bernhagen1,11, Regina Krohn2, Hongqi Lue1, Julia L Gregory3, Alma Zernecke2, Rory R Koenen2, Manfred Dewor1, Ivan Georgiev1, Andreas Schober4, Lin Leng5, Teake Kooistra6, Günter Fingerle-Rowson7, Pietro Ghezzi8, Robert Kleemann6,9, Shaun R McColl10, Richard Bucala5, Michael J Hickey3 & Christian Weber2,11
Abstract
The cytokine macrophage migration inhibitory factor (MIF) plays a critical role in inflammatory diseases and atherogenesis. We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF. MIF triggered G
i- and integrin-dependent arrest and chemotaxis of monocytes and T cells, rapid integrin activation and calcium influx through CXCR2 or CXCR4. MIF competed with cognate ligands for CXCR4 and CXCR2 binding, and directly bound to CXCR2. CXCR2 and CD74 formed a receptor complex, and monocyte arrest elicited by MIF in inflamed or atherosclerotic arteries involved both CXCR2 and CD74. In vivo, Mif deficiency impaired monocyte adhesion to the arterial wall in atherosclerosis-prone mice, and MIF-induced leukocyte recruitment required Il8rb (which encodes Cxcr2). Blockade of Mif but not of canonical ligands of Cxcr2 or Cxcr4 in mice with advanced atherosclerosis led to plaque regression and reduced monocyte and T-cell content in plaques. By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. Targeting MIF in individuals with manifest atherosclerosis can potentially be used to treat this condition.
- Department of Biochemistry and Molecular Cell Biology, Institute of Biochemistry, University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, D-52074 Aachen, Germany.
- Institute of Molecular Cardiovascular Research, University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, D-52074 Aachen, Germany.
- Centre for Inflammatory Diseases, Monash University, Victoria 3168, Australia.
- Medical Policlinic, Ludwig-Maximilians-University, D-80336 Munich, Germany.
- Department of Medicine, Pathology, Epidemiology and Public Health, The Anlyan Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
- TNO Quality of Life, Gaubius Laboratory/Biosciences, Department of Vascular and Metabolic Diseases, 2301 CE Leiden, The Netherlands.
- Medical Clinic I, Department of Hematology and Oncology, University Hospital Cologne, D-50937 Cologne, Germany.
- Mario Negri-Institute for Pharmacological Research, 20157 Milan, Italy.
- Department of Vascular Surgery, Leiden University Medical Center, 2333 CK Leiden, The Netherlands.
- School of Molecular and Biomedical Science, University of Adelaide, Adelaide SA 5005, Australia.
- These authors contributed equally to this work.
Correspondence to: Jürgen Bernhagen1,11 e-mail: jbernhagen@ukaachen.de
Correspondence to: Christian Weber2,11 e-mail: cweber@ukaachen.de
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