Macrophage Migration Inhibitory Factor (MIF)-Based Therapeutic Concepts in Atherosclerosis and Inflammation

What EXACTLY is your stroke doctor, stroke hospital and stroke association doing to get this completely tested in human clinical trials? And why are they doing nothing? 

Laziness? Incompetence? Or just don't care? No leadership? No strategy? Not my job?  The board of directors didn't tell them that totally solving stroke was their job, not just lazily relying on the status quo?

 

Macrophage Migration Inhibitory Factor (MIF)-Based Therapeutic Concepts in Atherosclerosis and Inflammation

Dzmitry Sinitski^*

,

Christos Kontos^*

,

Christine Krammer^*

,

Yaw Asare

,

Aphrodite Kapurniotu^**

,

Jürgen Bernhagen^**

› Author Affiliations Funding This work was supported by Deutsche Forschungsgemeinschaft (DFG) grant SFB1123-A03 to J.B. and A.K., SFB1123-B03 to Y.A. and by DFG within the framework of Munich Cluster for Systems Neurology (EXC 1010 SyNergy) to J.B.

Further Information

• Abstract
• Full Text
• References
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• Abstract
• Introduction
• MIF is a Chemokine-Like Inflammatory Mediator that Promotes Atherosclerosis
• MIF Proteins and Their Receptors
• Antibody-Based Anti-MIF Strategies
• Small Molecule Drug-Based Anti-MIF Strategies
• Peptide-Based Anti-MIF Strategies
• Conclusion
• References

Abstract

Chemokines orchestrate leukocyte recruitment in atherosclerosis and their blockade is a promising anti-atherosclerotic strategy, but few chemokine-based approaches have advanced into clinical trials, in part owing to the complexity and redundancy of the chemokine network. Macrophage migration inhibitory factor (MIF) is a pivotal mediator of atherosclerotic lesion formation. It has been characterized as an inflammatory cytokine and atypical chemokine that promotes atherogenic leukocyte recruitment and lesional inflammation through interactions with the chemokine receptors CXCR2 and CXCR4, but also exhibits phase-specific CD74-mediated cardioprotective activity. The unique structural properties of MIF and its homologue MIF-2/D-DT offer intriguing therapeutic opportunities including small molecule-, antibody- and peptide-based approaches that may hold promise as inhibitors of atherosclerosis, while sparing tissue-protective classical chemokine pathways. In this review, we summarize the pros and cons of anti-MIF protein strategies and discuss their molecular characteristics and receptor specificities with a focus on cardiovascular disease.

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Keywords

MIF - chemokine receptor - atypical chemokine - small molecule drug compound - peptide - antibody

Introduction

Atherosclerosis is a chronic inflammatory disease of our arteries that is characterized by the development of lipid-rich inflamed plaques in the vessel wall. Lesion progression and plaque rupture may result in detrimental cardiovascular events such as acute myocardial infarction and ischaemic stroke,[1] [2] the leading causes of death worldwide.[3] Influenced by genetic and environmental risk factors such as hyperlipidaemia, atherosclerosis is initiated by endothelial dysfunction, followed by an accumulation of oxidized low-density lipoproteins (oxLDLs) and an inflammatory cell infiltrate dominated by monocytes and T cells into the atherogenic vessel wall. Infiltrating monocytes differentiate into macrophages and lipid-laden foam cells. Lesion progression also involves vascular smooth muscle cell (VSMC) proliferation, necrotic core formation and wall remodelling that may eventually lead to plaque destabilization, rupture and thrombosis.[4]
These processes are mediated by inflammatory cytokines and chemokines at all stages. Some 50 classical chemokines interact with 18 G-protein-coupled receptor (GPCR)-type chemokine receptors. This network is characterized by a high degree of redundancy and promiscuity and chemokines are divided into CC-, CXC-, CX₃C- and C-type sub-classes and correspondingly termed receptors.[5] [6]
Due to their causal role in atherogenesis, anti-cytokine/-chemokine approaches are pursued as therapeutic strategies to attenuate atherosclerosis.[7] Several chemokine-blocking antibodies and chemokine receptor-inhibiting small molecule drug (SMD) compounds are in advanced pre-clinical testing and (early) clinical trial phases.[7] [8] [9] [10] [11] Importantly, the promising results obtained with an interleukin-1β (IL-1β)-blocking antibody in the CANTOS trial have validated the inflammatory hypothesis in atherosclerosis and demonstrated the power of cytokine-based anti-inflammatory drugs in patients with established atherosclerotic disease.[12]
Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine with chemokine-like characteristics and unique structural properties and is classified as a prototypical member of the emerging family of atypical chemokines (ACKs).[13] [14] [15] [16] ACKs lack the typical chemokine-fold and conserved N-terminal cysteines of classical chemokines,[6] but exhibit chemotactic activity and bind to classical chemokine receptors.[16] MIF is up-regulated in human atherosclerotic lesions[17] and its levels correlate with coronary artery disease (CAD).[18] [19] Mif gene deletion (Mif-KO) and antibody-based neutralization of MIF in experimental atherosclerosis suggest it is a major driver of atheroprogression during several stages of the disease.[14] [18]
Here, we discuss molecular strategies to inhibit MIF and its structural homologue D-dopachrome tautomerase (D-DT), also termed MIF-2, in atherosclerosis and other inflammatory diseases. We cover antibody-based strategies, small molecules directed at the unique MIF catalytic pocket around N-terminal proline-2 or at allosteric sites and emerging peptide-based approaches. The pros and cons of these strategies, potential side effects and envisaged receptor pathway specificities are compared.