Department of General Practice, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, United States.
Front Immunol. 2023 Sep 15;14:1219279. doi: 10.3389/fimmu.2023.1219279. eCollection 2023.
The transcription factor Fli-1, a member of the ETS family of transcription factors, is implicated in the pathogenesis of lupus disease. Reduced Fli-1 expression in lupus mice leads to decreased renal mRNA levels and renal infiltrating CXCR3+ T cells that parallels reduced renal inflammatory cell infiltration and renal damage. Inflammatory chemokine CXCL10 is critical for attracting inflammatory cells expressing the chemokine receptor CXCR3. The CXCL10/CXCR3 axis plays a role in the pathogenesis of various inflammatory diseases including lupus. Our data here demonstrate that renal CXCL10 protein levels are significantly lower in Fli-1 heterozygous MRL/ mice compared to wild-type MRL/ mice. Knockdown of Fli-1 significantly reduced CXCL10 secretion in mouse and human endothelial cells, and human mesangial cells, upon LPS or TNFα stimulation. The Fli-1 inhibitor, Camptothecin, significantly reduced CXCL10 production in human monocyte cells upon interferon stimulation. Four putative Ets binding sites in the promoter showed significant enrichment for FLI-1; however, FLI-1 did not directly drive transcription from the human or mouse promoters, suggesting FLI-1 may regulate CXCL10 expression indirectly. Our results also suggest that the DNA binding domain of FLI-1 is necessary for regulation of human promotor activity in human T cells and interactions with co-activators. Together, these results support a role for FLI-1 in modulating the CXCL10-CXCR3 axis by directly or indirectly regulating the expression of both genes to impact lupus disease development. Signaling pathways or drugs that reduce FLI-1 expression may offer novel approaches to lupus treatment.
转录因子 Fli-1 是 ETS 转录因子家族的成员，与狼疮病的发病机制有关。狼疮小鼠中 Fli-1 表达减少导致肾脏 mRNA 水平降低和肾脏浸润的 CXCR3+T 细胞减少，这与肾脏炎症细胞浸润和肾脏损伤减少相平行。炎症趋化因子 CXCL10 对于吸引表达趋化因子受体 CXCR3 的炎症细胞至关重要。CXCL10/CXCR3 轴在各种炎症性疾病的发病机制中起作用，包括狼疮。我们的数据表明，与野生型 MRL/小鼠相比，Fli-1 杂合 MRL/小鼠肾脏中的 CXCL10 蛋白水平明显降低。在 LPS 或 TNFα 刺激下，Fli-1 的敲低显著降低了小鼠和人内皮细胞以及人系膜细胞中 CXCL10 的分泌。Fli-1 抑制剂 Camptothecin 在干扰素刺激下人单核细胞中显著减少了 CXCL10 的产生。在 启动子中，四个推定的 Ets 结合位点对 FLI-1 表现出明显的富集；然而，FLI-1 并没有直接驱动人或鼠启动子的转录，这表明 FLI-1 可能间接调节 CXCL10 的表达。我们的结果还表明，FLI-1 的 DNA 结合域对于调节人 T 细胞中人类 启动子活性以及与共激活子的相互作用是必要的。总之，这些结果支持 FLI-1 通过直接或间接调节这两个基因的表达来调节 CXCL10-CXCR3 轴，从而影响狼疮病的发展。减少 FLI-1 表达的信号通路或药物可能为狼疮治疗提供新的方法。
