Macrophage depletion attenuates skin and kidney disease in lupus mice (BA7P.143)

Abstract

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of anti-nuclear autoantibodies and inflammatory damage in target organs, commonly the kidney and skin. Macrophages are thought to be important in the pathogenesis of lupus end organ disease, although studies to date have not been sufficiently conclusive. In this study, we investigated the role of macrophages in a spontaneous mouse model of SLE, the MRL/lpr mouse. PLX3397 (Plexxikon), a small molecule inhibitor of CSF1R, c-Kit, and FMS-like tyrosine kinase 3a, was administered in chow form to MRL/lpr mice starting at 9 weeks of age. Compared to matched control treated mice, PLX3397-treated MRL/lpr mice exhibited significantly less proteinuria and improved renal function. Furthermore, anti-dsDNA antibodies were significantly reduced at several time points. IBA-1 staining confirmed macrophage depletion within the kidneys of the PLX3397 treated mice. Interestingly, PLX3397-treated mice were also protected from the development of spontaneous skin lesions common to MRL/lpr mice, with control treated mice displaying significantly worse cutaneous disease macroscopically at 16 and 22 weeks of age. The improvement in skin lesions in PLX3397-treated mice was confirmed histologically in skin obtained at sacrifice. Our results indicate an important role for macrophages in the pathogenesis of skin and kidney disease in MRL/lpr mice, and implicate macrophages as a potential therapeutic target in SLE.