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Updated: Aug 15, 2026
Analyses of Proteinuria, Renal Infiltration of Leukocytes, and Renal Deposition of Proteins in Lupus-prone MRL/lpr Mice
Published on: June 8, 2022
Cultured mesangial cells from autoimmune MRL-lpr mice have decreased secreted and surface M-CSF
D C Brennan1, A M Jevnikar, R D Bloom
1Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Boston, Massachusetts.
Abstract:
M-CSF has been implicated in the pathogenesis of lupus nephritis in MRL-lpr mice. We recently reported persistently high levels of serum M-CSF in MRL-lpr mice as early as one week of age, not present in normal mice including C3H mice. In addition, M-CSF transcripts in MRL-lpr renal cortex increased with an increase in the severity of nephritis. Because glomerular mesangial cells (MC) secrete M-CSF, we investigated whether cultured MRL-lpr MC secrete more M-CSF than C3H MC. Paradoxically, unstimulated MRL-lpr MC secreted substantially less M-CSF than C3H MC [26 +/- 11 vs. 109 +/- 7 colony forming units (CFU)]. We then explored whether MC could express membrane bound M-CSF. We detected a 31 kDa form of membrane M-CSF on both MRL-lpr and C3H MC. Fewer MRL-lpr MC than C3H MC (24 +/- 5% vs. 78 +/- 5%) expressed membrane M-CSF. Furthermore, the increase in the mean channel log fluorescence intensity on MRL-lpr MC was considerably less than in C3H MC, indicating a lower density of M-CSF on MRL-lpr MC. Because our prior studies established that MRL-lpr kidneys have enhanced expression of TNF alpha, we stimulated cultured MC with TNF alpha. TNF alpha increased M-CSF secretion by stimulated MRL-lpr by twofold over unstimulated MRL-lpr MC, but did not increase M-CSF in C3H MC. In addition, M-CSF secretion was modestly greater in stimulated MRL-lpr MC compared to stimulated C3H MC. In conclusion, this is the first report of membrane M-CSF detectable on cultured MC. These studies note that despite higher circulating M-CSF and renal M-CSF transcripts in MRL-lpr mice, cultured MRL-lpr MC have lower basal secreted and membrane bound M-CSF than cultured C3H MC.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Despite higher M-CSF levels in lupus nephritis mice, their cultured kidney cells secrete less M-CSF. TNF-alpha stimulation partially restored M-CSF secretion in lupus cells, suggesting a complex role for M-CSF in nephritis.
Area of Science:
- Immunology
- Nephrology
- Cell Biology
Background:
- Macrophage colony-stimulating factor (M-CSF) is implicated in lupus nephritis pathogenesis.
- MRL-lpr mice, a model for lupus nephritis, exhibit persistently high serum M-CSF levels and increased renal M-CSF transcripts correlating with disease severity.
Purpose of the Study:
- To investigate the secretion and expression of M-CSF by cultured glomerular mesangial cells (MC) from MRL-lpr mice compared to normal C3H mice.
- To explore the effect of TNF-alpha on M-CSF secretion by MC.
Main Methods:
- Cultured MC from MRL-lpr and C3H mice were assessed for basal M-CSF secretion and expression of membrane-bound M-CSF.
- MC were stimulated with TNF-alpha to evaluate its impact on M-CSF secretion.
Main Results:
- Unstimulated MRL-lpr MC secreted significantly less M-CSF than C3H MC.
- MRL-lpr MC showed lower expression and density of membrane-bound M-CSF compared to C3H MC.
- TNF-alpha stimulation increased M-CSF secretion in MRL-lpr MC but not in C3H MC, leading to modestly greater M-CSF secretion in stimulated MRL-lpr MC.
Conclusions:
- This study reports the first detection of membrane-bound M-CSF on cultured MC.
- Despite elevated systemic M-CSF in MRL-lpr mice, their cultured MC exhibit reduced basal M-CSF secretion and membrane expression.
- TNF-alpha partially normalizes M-CSF secretion in MRL-lpr MC, indicating a complex regulatory mechanism in lupus nephritis.
