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Chemokine-like functions of MIF in atherosclerosis

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Abstract

The cytokine macrophage migration inhibitory factor (MIF) is a unique pro-inflammatory regulator of many acute and chronic inflammatory diseases. In the pathogenesis of atherosclerosis, chronic inflammation of the arterial wall characterized by chemokine-mediated influx of leukocytes plays a central role. The contribution of MIF to atherosclerotic vascular disease has come into focus of many studies in recent years. MIF is highly expressed in macrophages and endothelial cells of different types of atherosclerotic plaques, and functional studies established the contribution of MIF to lesion progression and plaque inflammation. This proatherogenic effect may partly be explained by the finding that MIF regulates inflammatory cell recruitment to lesion areas. Similar to chemokines, MIF induces integrin-dependent arrest and transmigration of monocytes and T cells. These chemokine-like functions are mediated through interaction of MIF with the chemokine receptors CXCR2 and CXCR4 as a non-canonical ligand. In atherogenic monocyte recruitment, MIF-induced monocyte adhesion involves CD74 and CXCR2, which form a signaling receptor complex. In addition to lesion progression, MIF has been implicated in plaque destabilization, since MIF is predominantly expressed in vulnerable plaques and can induce collagen-degrading matrix metalloproteinases. The latter could be a relevant mechanism in atherosclerotic abdominal aneurysm formation, where MIF expression is correlated with aneurysmal expansion. In summary, MIF has been identified as an important regulator of atherosclerotic vascular disease with exceptional chemokine-like functions. Detailed analysis of the interaction of MIF with its receptors could provide valuable information for drug development for the anti-inflammatory treatment of established and unstable atherosclerosis.

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Abbreviations

MIF:

macrophage migration inhibitory factor

CXCR2:

receptor for chemokines with an CXC motif (CXCL1, -2, -3, -8)

CXCR4:

receptor for the CXC chemokine CXCL12

CD74:

Invariant γ-chain of class II histocompatibility antigens

CXCL1:

chemokine ligand with a CXC motif; alternative titles: growth-regulated oncogene protein (GRO)-α, keratinocyte-derived chemokines (KC, mouse homolog)

CXCL8:

chemokine ligand with a CXC motif; alternative title: interleukin-8

CCL5:

chemokine ligand with a CC motif; alternative title: Regulated upon activation, normally T-expressed, and secreted (RANTES)

JAB-1:

jun-c activation domain-binding protein; binds intracellular MIF

AP-1:

activator protein-1; transcription factor involved in cellular proliferation, transformation and death

PDGF:

platelet-derived growth factor; affects migration and differentiation of smooth muscle cells

LDL-R−/− :

Low-density-Lipoprotein receptor deficient mice; develop hyperlipidemia and atherosclerosis on cholesterol-rich diet

ApoE−/− :

Apolipoprotein E-deficient mice; develop hyperlipidemia and atherosclerosis on cholesterol-rich diet

P-c-jun:

Phosphorylated c-jun transcription factor which activates AP-1 expression

C-EBP-β:

CCAAT/Enhancer-binding protein-β; transcription factor which determines expression of many Interleukin 6-dependent genes

αLβ2- integrin:

Heterodimeric leukocyte cell adhesion molecule with a β2- und αL subunit also referred to as leukocyte functional antigen (LFA)-1 or CD18/CD11c

α4β1-integrin:

Heterodimeric leukocyte cell adhesion molecule with a β1- und α4 subunit also referred to as very late activation protein (VLA)-4 or CD29/CD49d

CXCL12:

Chemokine ligand with a CXC motif, also known as stromal cell-derived factor (SDF)-1

CXCR1:

receptor for chemokines with a CXC motif (e.g. CXCL6, -8)

CXCR3:

receptor for chemokines with a CXC motif (e.g. CXCL9, -10, -11)

THP-1:

monocytic cell line derived from a patient with acute monocytic leukemia

MMP-1, -2, -9:

matrix metalloproteinases; Zn2+-binding endopeptidases that degrade various components of the extracellular matrix

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Authors and Affiliations

  1. Cardiology Unit, Medical Policlinic-City Center Campus, University of Munich, Munich, Germany

    Andreas Schober

  2. Department of Biochemistry and Molecular Cell Biology, Institute of Biochemistry, RWTH Aachen University, Aachen, Germany

    Jürgen Bernhagen

  3. Institute of Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany

    Christian Weber

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  1. Andreas Schober
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  2. Jürgen Bernhagen
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  3. Christian Weber
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Correspondence to Christian Weber.

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Schober, A., Bernhagen, J. & Weber, C. Chemokine-like functions of MIF in atherosclerosis. J Mol Med 86, 761–770 (2008). https://doi.org/10.1007/s00109-008-0334-2

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