Macrophage Migration Inhibitory Factor in Cardiovascular Disease

Abstract

Abstract-The highly conserved and archetypical yet atypical cytokine macrophage migration inhibitory factor (MIF) fulfills pleiotropic immune functions in many acute and chronic inflammatory diseases. Recent evidence has emerged from both expression and functional studies to implicate MIF in various aspects of cardiovascular disease. The present review is aimed at providing a synopsis of the involvement of MIF in the inflammatory pathogenesis of atherosclerosis and its consequences, namely unstable plaque formation, remodeling after arterial injury, aneurysm formation, myocardial infarction, or ischemia-reperfusion injury. In addition, other forms of myocardial dysfunction and inflammation and the role of MIF in angiogenesis are reviewed. The functional data are reconciled with recent progress in the identification of heptahelical (CXC chemokine) receptors for MIF, its prototypic role as their noncanonical ligand, and its signal transduction profile operative in atherogenic and inflammatory recruitment of mononuclear cells and in the oxidative damage and apoptosis of cardiomyocytes. Its unique features and functions clearly distinguish MIF from other cytokines implicated in atherogenesis and make it a prime target for achieving therapeutic regression of atherosclerosis.

Macrophage Migration Inhibitory Factor Triggers Chemotaxis of CD74+CXCR2+ NKT Cells in Chemically Induced IFN-γ–Mediated Skin Inflammation

“…To identify the factors required for chemotaxis of IFN-g-producing cells to sites of inflammation, we studied the role of MIF with respect to its potential effects in facilitating immune cell recruitment (13,14). We investigated whether MIF is released from epidermal keratinocytes upon TPA challenge, because TPA was proposed to cause cytotoxicity in keratinocytes (19).…”

“…However, it is still unclear which MIF receptors, including CD44, CD74, CXCR2, and CXCR4 (10,13,14), are expressed on CD56 + CD3 + hNKT cells. Therefore, magnetically isolated CD56 + cells were stained individually for CD3 and CD74, CD44, CXCR2, and CXCR4.…”

MIF and autophagy: a novel link beyond “eating”

“…The MIF protein is structurally unique, not belonging to any of the established cytokine families. In spite of the gross architectural homology between the CXCL8 dimer and the MIF monomer, MIF also does not formally belong to any of the four classical chemokine sub-families [4]. Owing to its cytokine/chemokine activities, MIF is a pivotal inflammatory mediator that has been implicated in acute and chronic inflammatory diseases including septic shock, rheumatoid arthritis, and atherosclerosis [3,5].…”

“…MIF was originally discovered as an inhibitor of random "macrophage" migration and as a promoter of the "phagocytotic" activity of these cells [3]. More recent data have established a critical role for MIF in inflam matory activation of macrophages, macrophage apoptosis, and inflammatory and atherogenic recruit ment of the macrophage precursor cell, the monocyte [3,4]. Thus, the "macrophage" continues to be in the center of MIF biology, but it also has become clear that MIF functions extend way beyond this cell type.…”

“…MIF has fairly unanimously been found to exert anti-apoptotic activities, yet the underlying mechanisms are not yet fully clear. Interestingly, the anti-apoptotic protein Bcl-2 has been shown to serve as a switch between the two cell death mechanisms and the MIF receptor CD74 has been found to be a potent activator of Bcl-2, at least in B cells [3,4].…”