Sundararaj Kamala P, Thiyagarajan Thirumagal, Molano Ivan, Basher Fahmin, Powers Thomas W, Drake Richard R, Nowling Tamara K
Division of Rheumatology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425;
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425; and.
J Immunol. 2015 Dec 15;195(12):5551-60. doi: 10.4049/jimmunol.1500961. Epub 2015 Nov 4.
The ETS factor Friend leukemia virus integration 1 (FLI1) is a key modulator of lupus disease expression. Overexpressing 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 strains (Fli1(+/-)) significantly improved kidney disease and prolonged survival. T cells from MRL/lpr Fli1(+/-) lupus mice have reduced activation and IL-4 production, neuraminidase 1 expression, and the levels of the glycosphingolipid lactosylceramide. In this study, we demonstrate that MRL/lpr Fli1(+/-) mice have significantly decreased renal neuraminidase 1 and lactosylceramide levels. This corresponds with a significant decrease in the number of total CD3(+) cells, as well as CD4(+) and CD44(+)CD62L(-) T cell subsets in the kidney of MRL/lpr Fli1(+/-) mice compared with the Fli1(+/+) nephritic mice. We further demonstrate that the percentage of CXCR3(+) T cells and Cxcr3 message levels in T cells are significantly decreased and correspond with a decrease in renal CXCR3(+) cells and in Cxcl9 and Cxcl10 expression in the MRL/lpr Fli1(+/-) compared with the Fli1(+/+) nephritic mice. Our results suggest that reducing the levels of FLI1 in MRL/lpr mice may be protective against development of nephritis in part through downregulation of CXCR3, reducing renal T cell infiltration and glycosphingolipid levels.
ETS 因子 Friend 白血病病毒整合 1（FLI1）是狼疮疾病表达的关键调节因子。在健康小鼠中过表达 FLI1 会导致一种类似于狼疮中观察到的自身免疫性肾病的发生。在两种狼疮品系（Fli1(+/-)）中降低 FLI1 的整体水平可显著改善肾病并延长生存期。来自 MRL/lpr Fli1(+/-)狼疮小鼠的 T 细胞活化和白细胞介素 -4 产生减少，神经氨酸酶 1 表达以及糖鞘脂乳糖神经酰胺水平降低。在本研究中，我们证明 MRL/lpr Fli1(+/-)小鼠的肾脏神经氨酸酶 1 和乳糖神经酰胺水平显著降低。这与 MRL/lpr Fli1(+/-)小鼠肾脏中总 CD3(+)细胞以及 CD4(+)和 CD44(+)CD62L(-) T 细胞亚群数量的显著减少相对应，与 Fli1(+/+)肾炎小鼠相比。我们进一步证明，与 Fli1(+/+)肾炎小鼠相比，MRL/lpr Fli1(+/-)小鼠中 CXCR3(+) T 细胞的百分比和 T 细胞中的 Cxcr3 信使水平显著降低，并且与肾脏中 CXCR3(+)细胞以及 Cxcl9 和 Cxcl10 表达的降低相对应。我们的结果表明，降低 MRL/lpr 小鼠中 FLI1 的水平可能部分通过下调 CXCR3、减少肾脏 T 细胞浸润和糖鞘脂水平来预防肾炎的发生。
