Circulating CSF-1 promotes monocyte and macrophage phenotypes that enhance lupus nephritis
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Updated: Jun 18, 2026
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Julia Menke1, Whitney A Rabacal, Katelyn T Byrne
1Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Abstract:
Macrophages mediate kidney disease and are prominent in a mouse model (MRL-Fas(lpr)) of lupus nephritis. Colony stimulating factor-1 (CSF-1) is the primary growth factor for macrophages, and CSF-1 deficiency protects MRL-Fas(lpr) mice from kidney disease and systemic illness. Whether this renoprotection derives from a reduction of macrophages and whether systemic CSF-1, as opposed to intrarenal CSF-1, promotes macrophage-dependent lupus nephritis remain unclear. Here, we found that increasing systemic CSF-1 hastened the onset of lupus nephritis in MRL-Fas(lpr) mice. Using mutant MRL-Fas(lpr) strains that express high, moderate, or no systemic CSF-1, we detected a much higher tempo of kidney disease in mice with the highest level of CSF-1. Furthermore, we uncovered a multistep CSF-1-dependent systemic mechanism central to lupus nephritis. CSF-1 heightened monocyte proliferation in the bone marrow (SSC(low)CD11b(+)), and these monocytes subsequently seeded the circulation. Systemic CSF-1 skewed the frequency of monocytes toward "inflammatory" (SSC(low)CD11b(+)Ly6C(high)) and activated populations that homed to sites of inflammation, resulting in a more rapid accumulation of intrarenal macrophages (CD11b(+)CSF-1R(+) or CD68(+)) that induced apoptosis of tubular epithelial cells, damaging the kidney. In humans, we found increased levels of CSF-1 in the serum, urine, and kidneys of patients with lupus compared with healthy controls. Furthermore, serum and urine CSF-1 levels correlated with lupus activity, and intrarenal CSF-1 expression correlated with the histopathology activity index of lupus nephritis. Taken together, circulating CSF-1 is a potential therapeutic target for lupus nephritis.
Insights
Systemic colony stimulating factor-1 (CSF-1) drives lupus nephritis by increasing inflammatory monocytes and kidney macrophages. Lowering CSF-1 may offer a therapeutic strategy for lupus nephritis.
Area of Science:
- Immunology
- Nephrology
- Molecular Biology
Background:
- Macrophages play a key role in mediating kidney disease, particularly in lupus nephritis.
- Colony stimulating factor-1 (CSF-1) is essential for macrophage development and function.
- The precise role of systemic versus intrarenal CSF-1 in lupus nephritis pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the impact of systemic CSF-1 levels on the development and progression of lupus nephritis.
- To elucidate the underlying CSF-1-dependent mechanisms driving macrophage accumulation and kidney damage.
- To explore the potential of CSF-1 as a therapeutic target for lupus nephritis.
Main Methods:
- Utilized MRL-Fas(lpr) mouse models with varying systemic CSF-1 levels.
- Analyzed monocyte proliferation, frequency, and homing characteristics in response to CSF-1.
- Quantified macrophage infiltration in the kidneys and assessed tubular epithelial cell apoptosis.
- Measured CSF-1 levels in human lupus patients' serum, urine, and kidney tissue.
Main Results:
- Increased systemic CSF-1 accelerated lupus nephritis onset and severity in mice.
- Systemic CSF-1 promoted bone marrow monocyte proliferation and skewed circulating monocytes towards inflammatory phenotypes.
- Elevated CSF-1 led to increased intrarenal macrophage accumulation, tubular cell apoptosis, and kidney damage.
- Human lupus patients exhibited higher CSF-1 levels, correlating with disease activity and kidney pathology.
Conclusions:
- Systemic CSF-1 is a critical driver of lupus nephritis pathogenesis through a multistep mechanism involving monocyte activation and kidney macrophage recruitment.
- Circulating CSF-1 levels are a potential biomarker for lupus nephritis activity and severity.
- Targeting systemic CSF-1 represents a promising therapeutic strategy for lupus nephritis.
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