Arrest Functions of the MIF Ligand/Receptor Axes in Atherogenesis

Abstract

Macrophage migration inhibitory factor (MIF) has been defined as an important chemokine-like function (CLF) chemokine with an essential role in monocyte recruitment and arrest. Adhesion of monocytes to the vessel wall and their transendothelial migration are critical in atherogenesis and many other inflammatory diseases. Chemokines carefully control all steps of the monocyte recruitment process. Those chemokines specialized in controlling arrest are typically immobilized on the endothelial surface, mediating the arrest of rolling monocytes by chemokine receptor-triggered pathways. The chemokine receptor CXCR2 functions as an important arrest receptor on monocytes. An arrest function has been revealed for the bona fide CXCR2 ligands CXCL1 and CXCL8, but genetic studies also suggested that additional arrest chemokines are likely to be involved in atherogenic leukocyte recruitment. While CXCR2 is known to interact with numerous CXC chemokine ligands, the CLF chemokine MIF, which structurally does not belong to the CXC chemokine sub-family, was surprisingly identified as a non-cognate ligand of CXCR2, responsible for critical arrest functions during the atherogenic process. MIF was originally identified as macrophage migration inhibitory factor (this function being eponymous), but is now known as a potent inflammatory cytokine with CLFs including chemotaxis and leukocyte arrest. This review will cover the mechanisms underlying these functions, including MIF’s effects on LFA1 integrin activity and signal transduction, and will discuss the structural similarities between MIF and the bona fide CXCR2 ligand CXCL8 while emphasizing the structural differences. As MIF also interacts with CXCR4, a chemokine receptor implicated in CXCL12-elicited lymphocyte arrest, the arrest potential of the MIF/CXCR4 axis will also be scrutinized as well as the recently identified role of pericyte MIF in attracting leukocytes exiting through venules as part of the pericyte “motility instruction program.”

Macrophage Migration Inhibitory Factor-CXCR4 Receptor Interactions

“…The extracellular activities involve binding and activation of CD74 and two chemokine receptors CXCR2 and CXCR4, which has led to the designation of MIF as both a cytokine and a non-cognate ligand of chemokine receptors. Other proteins that do not have any sequence or structural similarity to chemokines but activate chemokine receptors have been termed chemokine-like function chemokines or atypical chemokines, and they vary in their chemokine receptor specificity (25,26). Human ␤-defensin-1 binds to CCR6 and is chemotactic for immature dendritic cells; tyrosyl-tRNA synthetase is processed into a secreted agonist for CXCR1, histidyl-tRNA synthetase activates CCR5, and seryl-tRNA synthetase induces the migration of CCR3-transfected cells (62)(63)(64).…”

“…␤-Defensin-3, ubiquitin, peptucin analogs, as well as a complex between HMGB1 and CXCL12 have been reported as CXCR4 agonists or antagonists (65)(66)(67)(68). The structural basis underlying the engagement of chemokine receptors by these atypical chemokines is poorly understood and is likely to differ for each chemokine-like function because the structure of each protein does not share similarity with others (25).…”

“…100 M forskolin was applied to various CHO transfectants (wildtype and chimeras) in the presence or absence of MIF. This experiment also used forskolin and MIF with the MIF (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) or MIF(67-81) peptides to determine whether there is any competitive inhibition with MIF. After incubation for 30 min at 37°C and 5% CO 2 , chemiluminescence was measured in a standard microtiter plate reader.…”

“…Dysregulated MIF activity exacerbates autoimmune and inflammatory conditions, including septic shock, inflammatory lung diseases, autoimmune diseases, cancer, and atherogenesis (25)(26)(27)(28)(29)(30)(31). MIF contains an evolutionarily conserved catalytic cavity similar to microbial tautomerases/ isomerases that use Pro-1 as a catalytic base (32).…”

Deficiency of Endothelial Cxcr4 Reduces Reendothelialization and Enhances Neointimal Hyperplasia After Vascular Injury in Atherosclerosis-Prone Mice

“…Alternatively, it is possible that MIF, an alternative ligand for CXCR4, influences EC proliferation after injury through CXCR4, either by direct interaction or by binding its receptor CXCR2 in heterodimerization with CXCR4, for example, through joint interaction with CD74. 30 Such mitogenic effect of recombinant MIF on human coronary artery ECs was previously shown in vitro, although receptor involvement was not examined. 31 In addition to stimulating reendothelialization through migration and proliferation of vascular ECs, recruitment of EPCs to the injured site has been associated with efficient reendothelialization of denudated arteries, and transplantation or mobilization of EPCs has been linked with enhanced vascular repair after injury.…”