title: 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 was expressed at elevated levels, providing a potential mechanism for the reduction in MAPK phosphorylation in MIF-deficient cells. No increase in MAPK phosphatase-1 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. Additionally, 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 CCL2-induced macrophage adhesion and migration, and they indicate that MIF and CD74 mediate this effect via both common and independent mechanisms.
authors.affiliation: Department of Medicine, Centre for Inflammatory Diseases, Monash University, Monash Medical Centre, Clayton, Victoria 3168, Australia.
authors.forename: Huapeng
authors.initials: H
authors.lastname: Fan
authors.forename: Pam
authors.initials: P
authors.lastname: Hall
authors.forename: Leilani L
authors.initials: LL
authors.lastname: Santos
authors.forename: Julia L
authors.initials: JL
authors.lastname: Gregory
authors.forename: Gunter
authors.initials: G
authors.lastname: Fingerle-Rowson
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Eric F
authors.initials: EF
authors.lastname: Morand
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hickey
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000494:pharmacology; D018925:Chemokines / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism*; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D018925:Chemokines; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; C045084:invariant chain; D054638:Dual Specificity Phosphatase 1; D020741:rho GTP-Binding Proteins