The broad objective of this proposal is to test the hypothesis that increased intrarenal macrophage colony stimulating factor (CSF-1) expression is central to the pathogenesis of autoimmune renal disease in MRL-lpr/lpr mice. Using the MRL-lpr/lpr mouse with rapid, uniform, severe and predictable renal disease regulated by the lpr gene we will investigate the importance of CSF-1 in the pathogenesis of lupus nephritis. We propose to test whether the increase in circulating CSF-1 detected in neonatal MRL-lpr/lpr mice is contributed by the kidney alone or if other tissues are responsible for elevating serum levels. We will establish whether a molecule(s) in the circulation of MRL-lpr/lpr mice induces intrarenal CSF-1. We will determine whether increased renal expression of CSF-1 recruits macrophages. We will then investigate whether an increased expression of CSF-1 can induce renal disease in mice with normal kidneys including another strain with the lpr gene (C3H- lpr/lpr) and C3H-++ mice or accelerate an indolent, mild nephritis in congenic MRL-++, lacking the lpr gene. We will eliminate CSF-1 by creating a cytokine deficient MRL-lpr/lpr mouse and evaluate the impact on the development of lupus nephritis. In the event that the CSF-1 deficient MRL-lpr/lpr strain does not develop lupus nephritis we will determine if the inability of renal cells to express CSF-1 is responsible for preventing kidney disease. Through the advent of cellular and molecular techniques we now have the capacity to transfer a cytokine gene using a retroviral vector and establish tubular epithelial (TEC) and mesangial cell lines which can constitutively secrete high levels of a stable cytokine. By implanting these cells under the renal capsule we have created a system to introduce the continuing presence of CSF-1 (or other cytokines) into the kidney. We can then establish if CSF-1 recruits macrophages and determine whether CSF-1 will induce or accelerate renal injury in the MRL-++, C3H-lpr/lpr strains. To definitely establish whether CSF-1 or other cytokines have an enhanced glomerular expression prior to the influx of macrophages, we will isolate and pool individual glomeruli (glom) from MRL-lpr/lpr, congenic, and normal mice at varying ages and quantitate the level of cytokine and macrophages specific marker mRNA using the competitive template polymerase chain reaction. Finally, we will cross the MRL-++ or the C3H- lpr/lpr mice with CSF-1 transgenic mice and select for hybrids with these backgrounds overexpressing macrophage growth factors. In addition, we will eliminate CSF-1 from MRL-lpr/lpr mice by crossing them with the op/+ strain and select for a strain with op/op (producing a non-functional CSF-1) and lpr genes. By increasing or eliminating CSF-1, we will test the impact of this cytokine in promoting renal disease. In addition, we will use the approach of transplanting a kidney into a bilaterally nephrectomized recipient to determine when the MRL-lpr/lpr kidney is responsible for increasing serum CSF-1 and establish if this production is constitutive or is dependent on a stimulus. In addition, we will determine whether a circulating stimulant in the serum of MRL-lpr/lpr mice induces intrarenal CSF-1 and at what age this begins. Finally, we will test whether a kidney unable to express CSF-1 transplanted in the MRL-lpr/lpr mice develops renal injury. Taken together, using several novel approaches we will be able to clarify the importance of CSF-1 in the pathogenesis of lupus nephritis.
| Iwata, Yasunori; Boström, Elisabeth A; Menke, Julia et al. (2012) Aberrant macrophages mediate defective kidney repair that triggers nephritis in lupus-susceptible mice. J Immunol 188:4568-80 |
| Menke, Julia; Kriegsmann, Jörg; Schimanski, Carl Christoph et al. (2012) Autocrine CSF-1 and CSF-1 receptor coexpression promotes renal cell carcinoma growth. Cancer Res 72:187-200 |
| Menke, Julia; Iwata, Yasunori; Rabacal, Whitney A et al. (2011) Distinct roles of CSF-1 isoforms in lupus nephritis. J Am Soc Nephrol 22:1821-33 |
| Menke, Julia; Bork, Tillmann; Kutska, Birte et al. (2011) Targeting transcription factor Stat4 uncovers a role for interleukin-18 in the pathogenesis of severe lupus nephritis in mice. Kidney Int 79:452-63 |
| Menke, Julia; Rabacal, Whitney A; Byrne, Katelyn T et al. (2009) Circulating CSF-1 promotes monocyte and macrophage phenotypes that enhance lupus nephritis. J Am Soc Nephrol 20:2581-92 |
| Menke, Julia; Iwata, Yasunori; Rabacal, Whitney A et al. (2009) CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice. J Clin Invest 119:2330-42 |
| Menke, Julia; Zeller, Geraldine C; Kikawada, Eriya et al. (2008) CXCL9, but not CXCL10, promotes CXCR3-dependent immune-mediated kidney disease. J Am Soc Nephrol 19:1177-89 |
| Kelley, Vicki Rubin (2007) Leukocyte-renal epithelial cell interactions regulate lupus nephritis. Semin Nephrol 27:59-68 |
| Zeller, Geraldine C; Hirahashi, Junichi; Schwarting, Andreas et al. (2006) Inducible co-stimulator null MRL-Faslpr mice: uncoupling of autoantibodies and T cell responses in lupus. J Am Soc Nephrol 17:122-30 |
| Schwarting, Andreas; Paul, Kathrin; Tschirner, Stefan et al. (2005) Interferon-beta: a therapeutic for autoimmune lupus in MRL-Faslpr mice. J Am Soc Nephrol 16:3264-72 |
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