Bernhagen, J. et al. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat. Med. 13, 587-596

Department of Biochemistry and Molecular Cell Biology, Institute of Biochemistry, University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, D-52074 Aachen, Germany.
Nature Medicine (Impact Factor: 27.36). 06/2007; 13(5):587-96. DOI: 10.1038/nm1567
Source: PubMed


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.

Download full-text


Available from: Rory R Koenen
  • Source
    • "Following secretion, MIF binds to extracellular receptors, in particular the CD74 receptor, and is also internalized where it interacts with intracellular proteins. It has also been shown that MIF is a non-cognate ligand of the CXC chemokine receptors CXCR2 and CXCR4 [7] [8]. MIF exists as a homotrimeric protein and possesses ketoeenol tautomerase activity (against substrates L-dopachrome and phenylpyruvate), which is catalyzed by its N-terminal proline [9] [10]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has roles in the innate immune response, and also contributes to inflammatory disease. While the biological properties of MIF are closely linked to protein-protein interactions, MIF also has tautomerase activity. Inhibition of this activity interferes with the interaction of MIF with protein partners e.g. the CD74 receptor, and tautomerase inhibitors show promise in disease models including multiple sclerosis and colitis. Isothiocyanates inhibit MIF tautomerase activity via covalent modification of the N-terminal proline. We systematically explored variants of benzyl and phenethyl isothiocyanates, to define determinants of inhibition. In particular, substitution with hydroxyl, chloro, fluoro and trifluoro moieties at the para and meta positions were evaluated. In assays on treated cells and recombinant protein, the IC50 varied from 250 nM to >100 μM. X-ray crystal structures of selected complexes revealed that two binding modes are accessed by some compounds, perhaps owing to strain in short linkers between the isothiocyanate and aromatic ring. The variety of binding modes confirms the existence of two subsites for inhibitors and establishes a platform for the development of potent inhibitors of MIF that only need to target one of these subsites. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    Full-text · Article · Feb 2015 · European Journal of Medicinal Chemistry
  • Source
    • "Interestingly, although CXCL2 does not appear to promote monocyte migration in response to CXCL8, it does promote migration in response to its atypical ligand macrophage migration inhibitory factor (MIF). MIF binds to CD74 and CXCR2 on monocytes and macrophages, leading to CXCR2 signaling and integrin-dependent chemotaxis of monocytes, which is necessary for maintenance of atherosclerotic plaques (Bernhagen et al. 2007). Additionally, CCR1 and CCR5 have been shown to promote chemotaxis of CCR2 þ monocytes in in vitro experiments, but in vivo data are lacking (Weber et al. 2001; Le Borgne et al. 2006; Shi and Pamer 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chemokines are chemotactic cytokines that control the migration and positioning of immune cells in tissues and are critical for the function of the innate immune system. Chemokines control the release of innate immune cells from the bone marrow during homeostasis as well as in response to infection and inflammation. They also recruit innate immune effectors out of the circulation and into the tissue where, in collaboration with other chemoattractants, they guide these cells to the very sites of tissue injury. Chemokine function is also critical for the positioning of innate immune sentinels in peripheral tissue and then, following innate immune activation, guiding these activated cells to the draining lymph node to initiate and imprint an adaptive immune response. In this review, we will highlight recent advances in understanding how chemokine function regulates the movement and positioning of innate immune cells at homeostasis and in response to acute inflammation, and then we will review how chemokine-mediated innate immune cell trafficking plays an essential role in linking the innate and adaptive immune responses. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Preview · Article · Jan 2015 · Cold Spring Harbor perspectives in biology
  • Source
    • "Macrophage migration inhibitory factor (MIF) is a proinflammatory protein critically involved in plaque progression in coronary artery disease (CAD) by regulating monocyte recruitment towards atherosclerotic lesions [1]. It was recently shown that upregulation of MIF is associated with adhesion and accumulation of macrophages and foam cell transformation and that MIF plays a decisive role in plaque cellularity, vulnerability and rupture [2e4] complicated by subsequent coronary thrombosis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: Monocyte infiltration is a critical step in the pathophysiology of plaque instability in coronary artery disease (CAD). Macrophage migration inhibitory factor (MIF) is involved in atherosclerotic plaque progression and instability leading to intracoronary thrombosis. Gremlin-1 (Grem1) has been recently identified as endogenous inhibitor of MIF. To date there are no data on the clinical impact of this interaction in cardiovascular patients. Methods and results: Plasma levels of MIF and Grem1 were determined by enzyme-linked immunoassay in patients with acute coronary syndromes (ACS, n = 120; stable CAD, n = 166 and healthy control subjects, n = 25). MIF levels were significantly increased in ACS compared to stable CAD and healthy control (ACS: median 2.85; IQR 3.52 ng/ml; versus SAP: median 1.22; IQR 2.99 ng/ml; versus healthy control: median 0.10; IQR 0.09 ng/ml, p < 0.001). Grem1 levels were significantly higher in ACS and stable CAD patients compared to healthy control (ACS: median 211.00; IQR 130.47 ng/ml; SAP: median 220.20; IQR 120.93 ng/ml, versus healthy control: median 90.57; IQR 97.68 ng/ml, p < 0.001). Grem1/MIF ratio was independently associated with ACS, whereas the single parameters were not associated with the presence of ACS. Furthermore, Grem1/MIF ratio was associated with angiographic signs of intracoronary thrombi and severity of thrombus burden. Conclusion: These novel findings suggest a potential role of Grem1/MIF ratio to indicate acuity of CAD and the grade of plaque stability. Prospective angiographic cohort studies involving plaque imaging techniques are warranted to further characterize the prognostic role of this novel risk marker in CAD patients. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · Sep 2014 · Atherosclerosis
Show more