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Pivotal role of colony stimulating factor-1 in lupus nephritis
V Rubin Kelley1, R D Bloom, M A Yui
1Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Abstract:
Spontaneous autoimmune renal injury in MRL-lpr mice shares many features of human lupus nephritis. We noted a prominent increase of macrophages (M phi) in the glomerulus of MRL-lpr mice. Since colony stimulating factor-1 (CSF-1) regulates M phi growth and is a potent chemoattractant, we explored the possibility that there was an increase in CSF-1 in MRL-lpr mice. We detected a biphasic increase in circulating CSF-1 in MRL-lpr mice as compared to congenic MRL- ++ mice other strains with the lpr gene, and normal mice. There was an increase in CSF-1 steady state mRNA transcripts in the kidney but not in the liver, lung or bone marrow. By in situ hybridization our studies identified the glomeruli as the predominant source of renal CSF-1. Enhanced CSF-1 is expressed by the mesangial cells at the same time (4 weeks of age) that M phi begin to accumulate in the glomeruli, well in advance of the loss of renal function. We have isolated pure populations of glomerular M phi in culture from MRL-lpr mice. These glomerular M phi require CSF-1 to survive and proliferate. Therefore, these data suggest that CSF-1 is increased in the glomerulus prior to the influx and accumulation of M phi. We propose that CSF-1 expression in the kidney is pivotal in the attraction and accumulation of M phi and in turn responsible for initiating tissue destruction.
Insights
Colony-stimulating factor-1 (CSF-1) increases in MRL-lpr mouse kidneys, attracting macrophages to the glomeruli. This early increase in CSF-1 is linked to the onset of autoimmune kidney damage in lupus nephritis models.
Area of Science:
- Immunology
- Nephrology
- Molecular Biology
Background:
- MRL-lpr mice exhibit autoimmune renal injury resembling human lupus nephritis.
- Macrophages (M phi) are notably increased in the glomeruli of MRL-lpr mice.
- Colony-stimulating factor-1 (CSF-1) is a key regulator of macrophage proliferation and a chemoattractant.
Purpose of the Study:
- To investigate the role of CSF-1 in the pathogenesis of autoimmune kidney disease in MRL-lpr mice.
- To determine if increased CSF-1 levels correlate with macrophage accumulation in the kidneys.
- To identify the source of renal CSF-1.
Main Methods:
- Quantification of circulating CSF-1 levels in MRL-lpr mice and control groups.
- Measurement of CSF-1 mRNA transcripts in various organs.
- In situ hybridization to localize CSF-1 expression within the kidney.
- Culture of glomerular macrophages from MRL-lpr mice to assess CSF-1 dependence.
Main Results:
- A biphasic increase in circulating CSF-1 was observed in MRL-lpr mice.
- Elevated CSF-1 mRNA steady-state transcripts were found predominantly in the kidney.
- In situ hybridization identified glomeruli, specifically mesangial cells, as the primary source of renal CSF-1.
- Isolated glomerular macrophages from MRL-lpr mice require CSF-1 for survival and proliferation.
Conclusions:
- CSF-1 is significantly increased in the glomeruli of MRL-lpr mice prior to substantial macrophage influx.
- Glomerular CSF-1 expression appears pivotal in attracting and accumulating macrophages, initiating kidney tissue damage.
- Targeting CSF-1 may offer a therapeutic strategy for lupus nephritis.