Macrophage Migration Inhibitory Factor and CD74 Regulate Macrophage Chemotactic Responses via MAPK and Rho GTPase

Abstract

Macrophage migration inhibitory factor (MIF) promotes leukocyte recruitment to sites of inflammation. However, whether this stems from a direct effect on leukocyte migration is unknown. Furthermore, the role of the MIF-binding protein CD74 in this response has not been investigated. Therefore the aim of this study was to examine the contributions of MIF and CD74 to chemokine-induced macrophage recruitment. Intravital microscopy studies demonstrated that CCL2-induced leukocyte adhesion and transmigration were reduced in MIF−/− and CD74−/− mice. MIF−/− and CD74−/− macrophages also exhibited reduced chemotaxis in vitro, although CD74−/− macrophages showed increased chemokinesis. Reduced CCL2-induced migration was associated with attenuated MAPK phosphorylation, RhoA GTPase activity and actin polymerization in MIF−/− and CD74−/− macrophages. Furthermore, in MIF−/− macrophages, MAPK phosphatase-1 (MKP-1) was expressed at elevated levels, providing a potential mechanism for the reduction in MAPK phosphorylation in MIF-deficient cells. No increase in MKP1 expression was observed in CD74−/− macrophages. In in vivo experiments assessing the link between MIF and CD74, combined administration of MIF and CCL2 increased leukocyte adhesion in both MIF−/− and CD74−/− mice, showing that CD74 was not required for this MIF-induced response. In addition, although leukocyte recruitment induced by administration of MIF alone was reduced in CD74−/− mice, consistent with a role for CD74 in leukocyte recruitment induced by MIF, MIF-treated CD74−/− mice displayed residual leukocyte recruitment. These data demonstrate that MIF and CD74 play previously unappreciated roles in chemokine-induced macrophage adhesion and migration, and indicate that MIF and CD74 mediate this effect via both common and independent mechanisms.

Novel Anti-inflammatory Activity of Epoxyazadiradione against Macrophage Migration Inhibitory Factor

“…Epoxyazadiradione Inhibits MIF-mediated Macrophage Chemotactic Migration-MIF promotes macrophage chemotactic migration and plays an important role in leukocyte recruitment and inflammation (69). Inhibition of the tautomerase activity of MIF reduces inflammation induced by MIF (70,71).…”

Insights into the role of macrophage migration inhibitory factor in obesity and insulin resistance

“…Binding of MIF to CXCR4 on the surface of fibroblasts and T-cells induced JNK propagating CXCL8 secretion (115) . Intriguingly, an alternative MIF receptor CD74, traditionally involved in the activation of mitogen-activated protein kinases pathway, has recently been demonstrated to also mediate macrophage chemotactic responses (116) . Given its diverse functionality and prominent role in macrophage biology MIF has been implicated in a multitude of inflammatory diseases (107) .…”

Tyrosine Sulfation of Chemokine Receptor CCR2 Enhances Interactions with Both Monomeric and Dimeric Forms of the Chemokine Monocyte Chemoattractant Protein-1 (MCP-1)

“…In brief, mice were injected subcutaneously, adjacent to the cremaster muscle, with 345 ng of either wild type or mutant MCP-1, in 150 l of saline. Four hours later, the cremaster muscle was exteriorized for intravital microscopy as described previously (25). Three or four postcapillary venules (25-40 m in diameter) were examined in each animal, and leukocyte adhesion (cells/100 m venule length) and emigration (cells/field of view) were quantitated using standard techniques (25).…”

“…Leukocyte Adhesion and Emigration by Intravital Imaging-MCP-1-induced leukocyte adhesion and emigration were assessed as described previously (24,25). In brief, mice were injected subcutaneously, adjacent to the cremaster muscle, with 345 ng of either wild type or mutant MCP-1, in 150 l of saline.…”

“…CCR2 is a major chemokine receptor expressed on monocytes, and activation by its chemokine ligands monocyte chemoattractant proteins 1 to 4 (MCP-1 to -4; systematic names CCL2, CCL8, CCL7, and CCL13, respectively) 6 stimulates the migration of monocytes across the vascular wall into tissues where they mediate chronic inflammation (19). The tyrosine sulfation motif of CCR2 has the sequence 25 …”