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Increased macrophage colony-stimulating factor in neonatal and adult autoimmune MRL-lpr mice
M A Yui1, W H Brissette, D C Brennan
1Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Boston, Massachusetts.
Abstract:
Abnormal macrophages in MRL-lpr mice are implicated in the pathogenesis of autoimmune disease. These mice die of lupus nephritis by 5 to 6 months of age. This study reports that MRL-lpr mice have an increased level of circulating macrophage colony-stimulating factor (M-CSF) detectable as early as 1 week of age. Macrophage colony-stimulating factor decreased between 2 and 4 months and then steadily increased beginning at 4 months of age. In contrast, M-CSF was not detected in sera from congenic MRL-++ mice, normal C3H/FeJ mice, two other mouse strains with the lpr gene (B6-lpr and C3H-lpr), or another lupus model, the NZB/W mouse. These observations indicate that the lpr gene alone is not responsible for inducing this growth factor, and elevated M-CSF is not required for all forms of murine lupus. The entire source of serum M-CSF is not clear. The unique T cells regulated by the lpr gene are not responsible for the increased serum M-CSF levels, as no M-CSFs could be detected in supernatants from cultured lymph nodes from MRL-lpr mice, and the steady-state levels of M-CSF mRNA in lymph nodes and spleens in MRL-lpr, C3H-lpr mice and in their respective congenic strains were similar. The steady-state M-CSF mRNA transcripts in liver, lung, and bone marrow in MRL-lpr, MRL-++, and C3H/FeJ mice were also similar. Macrophage colony-stimulating factor transcripts were clearly elevated in the kidneys of MRL-lpr mice, suggesting a renal source of circulating M-CSF. The increase of M-CSF might be responsible for the increased numbers and enhanced functions of macrophages, which in turn cause tissue destruction in MRL-lpr mice.
Insights
MRL-lpr mice exhibit elevated circulating macrophage colony-stimulating factor (M-CSF) early in life, linked to lupus nephritis. This M-CSF increase, potentially from kidneys, may drive macrophage-driven tissue damage in autoimmune disease.
Area of Science:
- Immunology
- Autoimmune Diseases
- Molecular Biology
Background:
- Abnormal macrophages contribute to autoimmune disease pathogenesis.
- MRL-lpr mice develop lupus nephritis and succumb by 5-6 months of age.
Purpose of the Study:
- To investigate the role of macrophage colony-stimulating factor (M-CSF) in MRL-lpr mice.
- To determine if the lpr gene alone induces elevated M-CSF.
Main Methods:
- Quantified circulating M-CSF levels in MRL-lpr mice and control strains.
- Analyzed M-CSF mRNA expression in various tissues (lymph nodes, spleen, liver, lung, bone marrow, kidneys).
- Assessed M-CSF in lymph node culture supernatants.
Main Results:
- MRL-lpr mice showed increased circulating M-CSF from 1 week of age, with a biphasic pattern.
- M-CSF was not detected in congenic MRL-++ mice, normal C3H/FeJ, B6-lpr, C3H-lpr, or NZB/W mice.
- M-CSF mRNA levels were similar in lymphoid organs and non-kidney tissues but elevated in MRL-lpr kidneys.
Conclusions:
- Elevated M-CSF is specific to MRL-lpr mice and not solely caused by the lpr gene.
- The kidneys are a likely source of circulating M-CSF in MRL-lpr mice.
- Increased M-CSF may promote macrophage proliferation and function, leading to tissue destruction in lupus nephritis.