Bernhagen Jürgen, Krohn Regina, Lue Hongqi, Gregory Julia L, Zernecke Alma, Koenen Rory R, Dewor Manfred, Georgiev Ivan, Schober Andreas, Leng Lin, Kooistra Teake, Fingerle-Rowson Günter, Ghezzi Pietro, Kleemann Robert, McColl Shaun R, Bucala Richard, Hickey Michael J, Weber Christian
Department of Biochemistry and Molecular Cell Biology, Institute of Biochemistry, University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, D-52074 Aachen, Germany.
Nat Med. 2007 May;13(5):587-96. doi: 10.1038/nm1567. Epub 2007 Apr 15.
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.
细胞因子巨噬细胞移动抑制因子（MIF）在炎症性疾病和动脉粥样硬化形成过程中发挥关键作用。我们确定趋化因子受体CXCR2和CXCR4为MIF的功能性受体。MIF通过CXCR2或CXCR4触发G（αi）和整合素依赖性单核细胞和T细胞的停滞及趋化作用、快速整合素激活和钙内流。MIF与同源配体竞争CXCR4和CXCR2结合，并直接与CXCR2结合。CXCR2和CD74形成受体复合物，MIF在炎症或动脉粥样硬化动脉中引发的单核细胞停滞涉及CXCR2和CD74。在体内，Mif缺陷损害了易患动脉粥样硬化小鼠的单核细胞对动脉壁的黏附，且MIF诱导的白细胞募集需要Il8rb（其编码Cxcr2）。在患有晚期动脉粥样硬化的小鼠中，阻断Mif而非Cxcr2或Cxcr4的经典配体可导致斑块消退并减少斑块中的单核细胞和T细胞含量。通过激活CXCR2和CXCR4，MIF发挥趋化因子样功能，并作为炎症细胞募集和动脉粥样硬化形成的主要调节因子。在患有明显动脉粥样硬化的个体中靶向MIF可能可用于治疗这种病症。
