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PMID: 21411731 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Macrophage migration inhibitory factor and CD74 regulate macrophage chemotactic responses via MAPK and Rho GTPase.

Journal of immunology (Baltimore, Md. : 1950) ·Vol. 186 ·No. 8 ·2011-04-15 ·Pages 4915-24

Fan H, Hall P, Santos LL, Gregory JL, Fingerle-Rowson G, Bucala R, Morand EF, Hickey MJ

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.

MeSH Terms
Animals Antigens, Differentiation, B-Lymphocyte/genetics,metabolism Blotting, Western Cell Adhesion/drug effects Cell Adhesion Molecules/metabolism Cell Movement/drug effects Cells, Cultured Chemokine CCL2/pharmacology Chemokines/metabolism Chemotaxis, Leukocyte/drug effects Dual Specificity Phosphatase 1/genetics,metabolism Histocompatibility Antigens Class II/genetics,metabolism Leukocytes/drug effects,metabolism Macrophage Migration-Inhibitory Factors/genetics,metabolism Macrophages/cytology,drug effects,metabolism Mice Mice, Inbred C57BL Mice, Knockout Phosphorylation/drug effects Reverse Transcriptase Polymerase Chain Reaction rho GTP-Binding Proteins/metabolism
Chemicals
Antigens, Differentiation, B-Lymphocyte Cell Adhesion Molecules Chemokine CCL2 Chemokines Histocompatibility Antigens Class II Macrophage Migration-Inhibitory Factors invariant chain Dual Specificity Phosphatase 1 rho GTP-Binding Proteins
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Fan Huapeng
Department of Medicine, Centre for Inflammatory Diseases, Monash University, Monash Medical Centre, Clayton, Victoria 3168, Australia.
Hall Pam
Santos Leilani L
Gregory Julia L
Fingerle-Rowson Gunter
Bucala Richard
Morand Eric F
Hickey Michael J
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Article Info
Journal
Journal of immunology (Baltimore, Md. : 1950)
Abbr.
J Immunol
ISSN
1550-6606
DOI
10.4049/jimmunol.1003713
Published
2011-04-15
Epub
2011-00-16
Pages
4915-24
Language
English
Region
United States
NLM ID
2985117R
PMCID
PMC3388798
Subset
IM
Grants
NIAMS NIH HHS · R01 AR050498 · United States
External Links
PubMed source DOI: 10.4049/jimmunol.1003713 PMC Full Text View journal details
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