title: Macrophage Migration Inhibitory Factor Mediates Proliferative GN via CD74.
abstract: Pathologic proliferation of mesangial and parietal epithelial cells (PECs) is a hallmark of various glomerulonephritides. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that mediates inflammation by engagement of a receptor complex involving the components CD74, CD44, CXCR2, and CXCR4. The proliferative effects of MIF may involve CD74 together with the coreceptor and PEC activation marker CD44. Herein, we analyzed the effects of local glomerular MIF/CD74/CD44 signaling in proliferative glomerulonephritides. MIF, CD74, and CD44 were upregulated in the glomeruli of patients and mice with proliferative glomerulonephritides. During disease, CD74 and CD44 were expressed de novo in PECs and colocalized in both PECs and mesangial cells. Stress stimuli induced MIF secretion from glomerular cells in vitro and in vivo, in particular from podocytes, and MIF stimulation induced proliferation of PECs and mesangial cells via CD74. In murine crescentic GN, Mif-deficient mice were almost completely protected from glomerular injury, the development of cellular crescents, and the activation and proliferation of PECs and mesangial cells, whereas wild-type mice were not. Bone marrow reconstitution studies showed that deficiency of both nonmyeloid and bone marrow-derived Mif reduced glomerular cell proliferation and injury. In contrast to wild-type mice, Cd74-deficient mice also were protected from glomerular injury and ensuing activation and proliferation of PECs and mesangial cells. Our data suggest a novel molecular mechanism and glomerular cell crosstalk by which local upregulation of MIF and its receptor complex CD74/CD44 mediate glomerular injury and pathologic proliferation in GN.
authors.affiliation: Department of Pathology, Department of Nephrology and Immunology, and.
authors.forename: Sonja
authors.initials: S
authors.lastname: Djudjaj
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Aachen, Germany;
authors.forename: Hongqi
authors.initials: H
authors.lastname: Lue
authors.affiliation: Department of Nephrology and Immunology, and.
authors.forename: Song
authors.initials: S
authors.lastname: Rong
authors.affiliation: Department of Pathology, Department of Nephrology and Immunology, and.
authors.forename: Marios
authors.initials: M
authors.lastname: Papasotiriou
authors.affiliation: Department of Pathology, Department of Nephrology and Immunology, and.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Klinkhammer
authors.affiliation: Department of Nephrology and Immunology, and.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Zok
authors.affiliation: Department of Pathology, Department of Nephrology and Immunology, and.
authors.forename: Ole
authors.initials: O
authors.lastname: Klaener
authors.affiliation: Department of Nephrology and Immunology, and.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Braun
authors.affiliation: Division of Nephrology and Institute of Physiology, University of Zürich, Zürich, Switzerland;
authors.forename: Maja T
authors.initials: MT
authors.lastname: Lindenmeyer
authors.affiliation: Division of Nephrology and Institute of Physiology, University of Zürich, Zürich, Switzerland;
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut;
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.affiliation: Institute of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn, Germany; and.
authors.forename: Andre P
authors.initials: AP
authors.lastname: Tittel
authors.affiliation: Institute of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn, Germany; and.
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.affiliation: Department of Nephrology and Immunology, and.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Moeller
authors.affiliation: Department of Nephrology and Immunology, and.
authors.forename: Juergen
authors.initials: J
authors.lastname: Floege
authors.affiliation: Department of Nephrology and Immunology, and.
authors.forename: Tammo
authors.initials: T
authors.lastname: Ostendorf
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Aachen, Germany; pboor@ukaachen.de jbernhagen@ukaachen.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bernhagen
authors.affiliation: Department of Pathology, Department of Nephrology and Immunology, and Institute of Molecular Biomedicine, Comenius University, Bratislava, Slovakia pboor@ukaachen.de jbernhagen@ukaachen.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Boor
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005921:Glomerulonephritis / Q000209:etiology* / Q000473:pathology; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D007678:Kidney Glomerulus / Q000166:cytology; D008263:Macrophage Migration-Inhibitory Factors / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; C045084:invariant chain
keywords: CD44; crescentic GN; mesangial cells; migration inhibitory factor; parietal epithelial cells; proliferation