MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment.
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.
Bernhagen
Jürgen
J
Department of Biochemistry and Molecular Cell Biology, Institute of Biochemistry, University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, D-52074 Aachen, Germany.
Krohn
Regina
R
Lue
Hongqi
H
Gregory
Julia L
JL
Zernecke
Alma
A
Koenen
Rory R
RR
Dewor
Manfred
M
Georgiev
Ivan
I
Schober
Andreas
A
Leng
Lin
L
Kooistra
Teake
T
Fingerle-Rowson
Günter
G
Ghezzi
Pietro
P
Kleemann
Robert
R
McColl
Shaun R
SR
Bucala
Richard
R
Hickey
Michael J
MJ
Weber
Christian
C
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
D008024:Ligands; D008263:Macrophage Migration-Inhibitory Factors; D019718:Receptors, CXCR4; D023063:Receptors, Interleukin-8B