Background/Purpose: Kidney and skin involvement are common in systemic lupus erythematosus (SLE). Nephritis is seen in up to 60% of patients, and contributes significantly to morbidity and mortality. Approximately 80% of patients manifest some form of cutaneous lupus erythematosus (CLE), and there is a strong correlation between rash and ultraviolet light-B (UVB) exposure. Macrophages contribute to the pathogenesis of nephritis and are correlated with poor outcomes. Furthermore, following UVB exposure, macrophages are increased in the skin where they contribute to keratinocyte apoptosis.  

Methods: To evaluate the role of macrophages in the pathogenesis of kidney and skin disease in murine SLE, we depleted macrophages using GW2580, a kinase inhibitor specific for colony stimulating-factor 1 receptor (CSF-1R). CSF-1R is found almost exclusively on macrophages and is important for their survival, recruitment, and activation. Lupus-prone female MRL/lpr mice (10 weeks of age) were treated with GW2580 (n=9) (or control, n=10) for 6 weeks via oral gavage. We tracked the development of kidney disease by measuring proteinuria, and assessed kidney function at 17 weeks of age by measuring serum BUN levels. In a separate cohort, female MRL/lpr mice (10 weeks of age) were exposed to two doses of UVB irradiation (50 mJ/cm²each), 24 hours apart, following 2 weeks of GW2580 or control treatment (GW2580, n=5; PBS, n=6).  Histology was blindly scored to assess skin damage.

Results: Macrophage depletion in MRL/lpr mice ameliorated kidney disease. Proteinuria in GW2580-treated mice was significantly lower, at multiple time points, than that seen in PBS-treated mice (13 weeks, GW2580=18±9.6 mg/dl, PBS=82±22 mg/dl, p-value=0.02; 15 weeks, GW2580=40±11.1 mg/dl, PBS=168±39.3 mg/dl, p-value=0.006). Macrophage depletion treatment also led to improved kidney function, with lower BUN levels in GW2580 as compared to control-treated mice at 17 weeks of age (GW2580=90±4.5 mg/dl, PBS=110±6.6 mg/dl, p-value=0.02). Anti-double stranded DNA antibody levels did not differ between the two groups of mice. Following macrophage depletion and subsequent UVB irradiation, MRL/lpr mice treated with GW2580 developed less severe skin lesions than those treated with PBS (mean skin scores: GW2580=2.3±0.12, PBS=4.6±0.2, p-value=0.0001). Classic characteristics of lupus-associated cutaneous disease such as hyperkeratosis and acanthosis were less prevalent in GW-treated mice.

Conclusion: Our studies support a role for macrophages in the pathogenesis of both kidney and skin disease in SLE. As current therapies are largely immunosuppressive and non-specific, these cells may represent a promising therapeutic target for LN and CLE treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/macrophage-depletion-using-a-specific-csf-1r-kinase-inhibitor-ameliorates-kidney-and-skin-disease-in-a-mouse-model-of-systemic-lupus-erythematosus/