The role of Fli1 in lupus T cell function and nephritis in MRL/lpr lupus prone mice (IRM11P.634)

Abstract

Abstract The Ets factor Fli1 is implicated as a key modulator of lupus disease expression. Over-expressing Fli1 in healthy mice, results in the development of an autoimmune kidney disease similar to that observed in lupus. Lowering the global levels of Fli1 in two lupus mouse models significantly improved kidney disease and prolonged survival. We recently demonstrated that lowering the global levels of Fli1 in MRL/lpr lupus mice (Fli1+/-) reduced T cell activation and IL-4 production. This was likely a result of decreased glycosphingolipid (GSL) metabolism, specifically decreased Neuraminidase1 (Neu1) expression and activity and decreased levels of the GSL lactosylceramide (LacCer) in the Fli1+/- T cells. GSLs are a heterogeneous class of lipids in the sphingolipid family that play a role in the regulation of cellular processes. Neu1 is an enzyme that mediates the GSL catabolic pathway. Here we demonstrate that MRL/lpr Fli1+/- T cells have significantly decreased: 1) levels of CXCR3 message, 2) percentage that are CXCR3+, 3) migration to the kidney and 4) renal Neu1 and LacCer levels, which we showed are significantly elevated in nephritic mice and humans with lupus. IHC staining shows that increased LacCer levels co-localize with T cells in the glomeruli. Together, our data demonstrate that reducing Fli1 levels in lupus T cells partially normalizes GSL metabolism in the kidney that is likely due in part to a reduction in T cell activation and migration to the kidney.