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

Xuan Wang1,2, Mara Lennard Richard2, Tomika S Caldwell2

  • 1Department of General Practice, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Frontiers in Immunology
|October 4, 2023
PubMed

Insights

Reduced Fli-1 expression impacts lupus by altering CXCL10 and CXCR3 levels, suggesting new therapeutic targets for lupus disease.

Area of Science:

  • Immunology
  • Molecular Biology
  • Rheumatology

Background:

  • The transcription factor Fli-1 (Friend Leukemia Integration 1) is involved in lupus pathogenesis.
  • Reduced Fli-1 expression correlates with decreased renal CXCL10 and CXCR3+ T cells in lupus models.
  • The CXCL10/CXCR3 axis is crucial in inflammatory diseases like lupus.

Purpose of the Study:

  • To investigate the role of Fli-1 in regulating the CXCL10/CXCR3 axis in lupus.
  • To explore Fli-1's direct or indirect mechanisms in controlling CXCL10 and CXCR3 expression.

Main Methods:

  • Analysis of renal CXCL10 protein levels in Fli-1 heterozygous MRL/lpr mice.
  • Fli-1 knockdown experiments in endothelial, mesangial, and monocyte cells.
  • Assessment of Fli-1 inhibitor (Camptothecin) effects on CXCL10 production.
  • ChIP-qPCR and reporter assays to evaluate Fli-1 binding and transcriptional activity on Cxcl10 and Cxcr3 promoters.

Main Results:

  • Renal CXCL10 protein levels were significantly lower in Fli-1 heterozygous MRL/lpr mice.
  • Fli-1 knockdown reduced CXCL10 secretion in various cell types upon stimulation.
  • Camptothecin treatment decreased CXCL10 production in human monocytes.
  • Fli-1 binding sites were enriched in the Cxcl10 promoter, but direct transcription was not observed; Fli-1's DNA binding domain was essential for regulating hCXCR3 promoter activity.

Conclusions:

  • Fli-1 modulates the CXCL10-CXCR3 axis, impacting lupus development through direct or indirect regulation of both genes.
  • Targeting Fli-1 expression or activity may offer novel therapeutic strategies for lupus.
Keywords:
CXCL10CXCR3chemokinefriend leukemia virus integration 1 transcription factorinflammationlupus nephritis

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