Role of the transcription factor Fli-1 on the CXCL10/CXCR3 Axis*

Frontiers in Immunology

Immunology

Xuan Wang¹  Xian K. Zhang²  Kamala Sundararaj²  Mara Lennard Richard²  Tomika S. Caldwell²  Tamara K. Nowling²  Shuzo Sato³ 

[1] 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;Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, United States;Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan;

关键词: CXCL10;    CXCR3;    chemokine;    friend leukemia virus integration 1 transcription factor;    inflammation;    lupus nephritis;   

DOI  :  10.3389/fimmu.2023.1219279

 received in 2023-05-08, accepted in 2023-08-29,  发布年份 2023

来源: Frontiers

【 摘 要 】

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 Cxcl10 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/lpr mice compared to wild-type MRL/lpr 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 Cxcl10 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 hCXCR3 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.

【 授权许可】

Unknown   
Copyright © 2023 Wang, Richard, Caldwell, Sundararaj, Sato, Nowling and Zhang