title: MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment.
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(alphai)- 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.
authors: Department of Biochemistry and Molecular Cell Biology, Institute of Biochemistry, University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, D-52074 Aachen, Germany.
authors: Jürgen
authors: J
authors: Bernhagen
authors: Regina
authors: R
authors: Krohn
authors: Hongqi
authors: H
authors: Lue
authors: Julia L
authors: JL
authors: Gregory
authors: Alma
authors: A
authors: Zernecke
authors: Rory R
authors: RR
authors: Koenen
authors: Manfred
authors: M
authors: Dewor
authors: Ivan
authors: I
authors: Georgiev
authors: Andreas
authors: A
authors: Schober
authors: Lin
authors: L
authors: Leng
authors: Teake
authors: T
authors: Kooistra
authors: Günter
authors: G
authors: Fingerle-Rowson
authors: Pietro
authors: P
authors: Ghezzi
authors: Robert
authors: R
authors: Kleemann
authors: Shaun R
authors: SR
authors: McColl
authors: Richard
authors: R
authors: Bucala
authors: Michael J
authors: MJ
authors: Hickey
authors: Christian
authors: C
authors: Weber
mesh_terms: D001011:Aorta; D050197:Atherosclerosis / Q000503:physiopathology*; D002633:Chemotaxis; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D007962:Leukocytes / Q000502:physiology; D008024:Ligands; D008263:Macrophage Migration-Inhibitory Factors / Q000494:pharmacology / Q000502:physiology*; D009000:Monocytes / Q000502:physiology; D019718:Receptors, CXCR4 / Q000502:physiology*; D023063:Receptors, Interleukin-8B / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology
chemical_list: D008024:Ligands; D008263:Macrophage Migration-Inhibitory Factors; D019718:Receptors, CXCR4; D023063:Receptors, Interleukin-8B