Macrophage Migration Inhibitory Factor Mediates Proliferative GN via CD74

作者：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 Juergen^*; Boor Peter^*

来源：Journal of the American Society of Nephrology, 2016, 27(6): 1650-1664.

DOI：10.1681/ASN.2015020149

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.

• 出版日期2016-6