Macrophage Migration Inhibitory Factor Mediates Proliferative GN via CD74
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Macrophage Migration Inhibitory Factor Mediates Proliferative GN via CD74. / Djudjaj, Sonja; Lue, Hongqi; Rong, Song; Papasotiriou, Marios; Klinkhammer, Barbara M; Zok, Stephanie; Klaener, Ole; Braun, Gerald S; Lindenmeyer, Maja T; Cohen, Clemens D; Bucala, Richard; Tittel, Andre P; Kurts, Christian; Moeller, Marcus J; Floege, Juergen; Ostendorf, Tammo; Bernhagen, Jürgen; Boor, Peter.
in: J AM SOC NEPHROL, Jahrgang 27, Nr. 6, 06.2016, S. 1650-64.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Macrophage Migration Inhibitory Factor Mediates Proliferative GN via CD74
AU - Djudjaj, Sonja
AU - Lue, Hongqi
AU - Rong, Song
AU - Papasotiriou, Marios
AU - Klinkhammer, Barbara M
AU - Zok, Stephanie
AU - Klaener, Ole
AU - Braun, Gerald S
AU - Lindenmeyer, Maja T
AU - Cohen, Clemens D
AU - Bucala, Richard
AU - Tittel, Andre P
AU - Kurts, Christian
AU - Moeller, Marcus J
AU - Floege, Juergen
AU - Ostendorf, Tammo
AU - Bernhagen, Jürgen
AU - Boor, Peter
N1 - Copyright © 2016 by the American Society of Nephrology.
PY - 2016/6
Y1 - 2016/6
N2 - 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.
AB - 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.
KW - Animals
KW - Antigens, Differentiation, B-Lymphocyte
KW - Cell Proliferation
KW - Cells, Cultured
KW - Female
KW - Glomerulonephritis
KW - Histocompatibility Antigens Class II
KW - Kidney Glomerulus
KW - Macrophage Migration-Inhibitory Factors
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
KW - Research Support, N.I.H., Extramural
U2 - 10.1681/ASN.2015020149
DO - 10.1681/ASN.2015020149
M3 - SCORING: Journal article
C2 - 26453615
VL - 27
SP - 1650
EP - 1664
JO - J AM SOC NEPHROL
JF - J AM SOC NEPHROL
SN - 1046-6673
IS - 6
ER -