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.”
Highlights
Leukocyte recruitment and arrest are central steps in inflammatory reactions and associated diseases, including atherosclerosis (Box 1)
There was a raising need to establish an additional chemokine category, to accomodate proteins that exhibit similar functions as the prototypical, “classical” chemokines, but that lack the typical chemokine structure. Characteristics of this group of “chemokine-like function (CLF) – chemokines” were defined as follows: (i) chemokinelike function (CLF) chemokines are released during infection, inflammation, or cell stress by non-classical export or due to cell death; (ii) they do not usually share the typical chemokine fold and the N-terminal residues with the classical chemokines; (iii) they exhibit chemokine-like activities in particular promoting chemotaxis; and (iv) they typically interact with a G protein-coupled receptor (GPCR), preferentially functioning as non-cognate ligand of a classical chemokine receptor (Degryse and de Virgilio, 2003; Yang et al, 2004; Oppenheim and Yang, 2005; Noels et al, 2009)
CONCLUDING REMARKS migration inhibitory factor (MIF) has been recognized as an important CLF chemokine mediating leukocyte recruitment and arrest in the context of many inflammatory diseases, in particular atherosclerosis
Summary
Leukocyte recruitment and arrest are central steps in inflammatory reactions and associated diseases, including atherosclerosis (Box 1). Exceed half of what was observed in the bone marrow-specific Cxcr knock-out (Boisvert et al, 2006), suggesting the presence of other relevant Cxcr ligands with an important role in monocyte recruitment during atherogenesis. One such factor was uncovered a year later and was found to be the inflammatory cytokine macrophage migration inhibitory factor (MIF). The migration inhibitory activity of MIF was not studied and characterized much further, the eponymous name “MIF” was kept up over the years It was largely unexpected, when MIF was identified as a ligand of CXCR2, exhibiting chemokinelike properties, and shown to be a crucial pro-atherogenic factor (Bernhagen et al, 2007).
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