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

ABSTRACT: 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.

SUBMITTER: Wang X

PROVIDER: S-EPMC10543418 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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

Wang Xuan X Richard Mara Lennard ML Caldwell Tomika S TS Sundararaj Kamala K Sato Shuzo S Nowling Tamara K TK Zhang Xian K XK

Frontiers in immunology 20230915

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 <i>Cxcl10</i> 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 th ...[more]

PMID: 37790939

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Project description:Coxsackievirus A2 (CVA2) is an emerging pathogen that results in hand-foot-and-mouth disease (HFMD) outbreaks. Systemic inflammatory response and central nervous system inflammation are the main pathological features of fatal HFMD. However, the immunopathogenesis of CVA2 infection is poorly understood. We first detected the transcriptional levels of 81 inflammation-related genes in neonatal mice with CVA2 infection. Remarkably, CVA2 induced higher expression of chemokine (C-X-C motif) ligand 10 (CXCL10) in multiple organs and tissues. CXCL10 acts through its cognate receptor chemokine (C-X-C motif) receptor 3 (CXCR3) and regulates immune responses. CXCL10/CXCR3 activation contributes to the pathogenesis of many inflammatory diseases. Next, we found CXCL10 and CXCR3 expression to be significantly elevated in the organs and tissues from CVA2-infected mice at 5 days postinfection (dpi) using immunohistochemistry (IHC). To further explore the role of CXCL10/CXCR3 in CVA2 pathogenesis, an anti-CXCR3 neutralizing antibody (αCXCR3) or IgG isotype control antibody was used to treat CVA2-infected mice on the same day as infection and every 24 h until 5 dpi. Our results showed that αCXCR3 therapy relieved the clinical manifestations and pathological damage and improved the survival rate of CVA2-infected mice. Additionally, αCXCR3 treatment reduced viral loads and reversed the proinflammatory cytokine (interleukin 6 [IL-6], tumor necrosis factor alpha [TNF-α], and IL-1β) expression, apoptosis, and inflammatory cell infiltration induced by CVA2. Collectively, our study presents evidence for the involvement of the CXCL10/CXCR3 axis in CVA2 pathogenesis. The activation of CXCL10/CXCR3 contributes to CVA2 pathogenesis by inducing apoptosis, proinflammatory cytokine expression, and inflammatory cell infiltration, which can be reversed by αCXCR3 therapy. This study provides new insight into the pathogenesis of HFMD, which has an important guiding significance for the treatment of HFMD. IMPORTANCE Systemic inflammatory response and central nervous system inflammation are the main pathological features of fatal HFMD cases. We detected the expression of 81 inflammation-related genes and found higher expression of CXCL10 in CVA2-infected mice. Next, we confirmed CXCL10/CXCR3 activation using immunohistochemistry and found that anti-CXCR3 neutralizing antibody (αCXCR3) therapy could relieve the clinical manifestations and pathological damage and improve the survival rate of CVA2-infected mice. Additionally, αCXCR3 treatment reduced viral loads and reversed the proinflammatory cytokine (IL-6, TNF-α, and IL-1β) expression, apoptosis, and inflammatory cell infiltration induced by CVA2. Collectively, our study presents the first evidence for the involvement of the CXCL10/CXCR3 axis in CVA2 pathogenesis. The activation of CXCL10/CXCR3 contributes to CVA2 pathogenesis via inducing apoptosis, proinflammatory cytokine expression, and inflammatory cell infiltration, which can be reversed by αCXCR3 therapy. This study provides new insight into the pathogenesis of HFMD, which has an important guiding significance for the treatment of HFMD.

Dataset Information

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

Publications

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

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