Background/Purpose  

Kidney involvement affects up to 60% of lupus patients, and is responsible for significant morbidity and mortality. Previous studies using a variety of methods to reduce the number of macrophages have reached conflicting conclusions regarding the role of macrophages in lupus nephritis (LN). Moreover, “off target” effects occur in mice congenitally deficient in macrophages. In this study we investigated the role of macrophages in an inducible model of LN, using a novel depletion method that minimized the confounding factors seen in previous studies.

Methods

To determine the role of macrophages in the antibody mediated nephritis associated with lupus, we utilized the nephrotoxic serum nephritis model. This is an inducible model of nephritis which closely mimics LN, and which is often used to model immune complex mediated renal disease. Mice received nephrotoxic serum (NTS) containing rabbit anti-mouse glomerular antibodies which deposited within the kidney to initiate nephritis. GW2580, an oral kinase inhibitor monospecific for the CSF-1 receptor, was used as a novel and highly selective method for macrophage depletion. GW2580 was delivered via oral gavage over a 10 day period (n=18). A second group of mice received a control gavage of PBS in addition to the NTS transfer (n=18). A third group was neither gavaged nor given NTS, and served as a healthy control population (n=9).

Results

We found that NTS challenged mice, when treated with GW2580 from day 0, did not develop the significant increases in proteinuria, serum creatinine or BUN seen in control treated mice. Furthermore, GW2580 treated mice were protected from the robust kidney expression of inflammatory cytokines associated with LN seen in control treated mice, including RANTES, IP-10, VCAM-1, MCP-1 and IL-6. Flow cytometry analysis of kidney single cell suspensions revealed a significant decrease in inflammatory macrophages (CD11b⁺F480^lo) in GW2580 treated mice. Furthermore, IBA-1 staining confirmed profound depletion of macrophages within glomeruli of treated mice. There was no significant change in circulating monocyte numbers with GW2580 treatment; however, there was a significant decrease in the number of macrophages in the spleen. Importantly, GW2580 did not interfere with the induction of the disease model. Finally, treatment with GW2580 at a later time point in the disease model (beginning day 5) was also effective at attenuating nephritis.  

Conclusion

Our results support an important role of macrophages in LN pathogenesis, and suggest targeting this cell type as a promising approach to the treatment of LN.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/macrophage-depletion-ameliorates-nephritis-induced-by-pathogenic-antibodies/