The impact of Fli1 deficiency on the pathogenesis of systemic sclerosis

Abstract

Systemic sclerosis (SSc) is an autoimmune inflammatory disease with unknown etiology characterized by microvascular injury and fibrosis of the skin and internal organs. A growing body of evidence suggests that deficiency of the transcription factor Fli1 (Friend leukemia integration-1) has a pivotal role in the pathogenesis of SSc. Fli1 is expressed in fibroblasts, endothelial cells, and immune cells, and has important roles in the activation, differentiation, development, and survival of these cells. Previous studies demonstrated that Fli1 is downregulated in SSc fibroblasts by an epigenetic mechanism and a series of experiments with Fli1-deficient animal models revealed that Fli1 deficiency in fibroblasts and endothelial cells reproduces the histopathologic features of fibrosis and vasculopathy in SSc, respectively. In this article, we review the impact of Fli1 deficiency on the pathogenesis of SSc and discuss a new therapeutic strategy for SSc by targeting the transcription factor Fli1.

Fig. 1

Schematic model of the TGF-β-induced post-translational modifications of Fli1. In quiescent fibroblasts, collagen gene expression is repressed by Fli1 occupancy of the collagen promoter. In response to TGF-β stimulation, PKC-δ is translocated into the nucleus and recruited to the COL1A2 promoter leading to phosphorylation of Fli1 at threonine 312. Phosphorylation of Fli1 is required for the subsequent PCAF-mediated acetylation of Fli1 at lysine 380. Acetylated Fli1 dissociates from the collagen promoter and is rapidly degraded through the proteasomal pathway, thereby enhancing collagen gene transcription.

Fig. 2

TGF-β coordinately regulates DNA binding activity of the transcriptional activator “Smad3” and the repressor “Fli1”. Upon TGF-β stimulation, Fli1 loses the transcriptional inhibitory effect on the COL1A2 promoter through a phosphorylation-acetylation cascade, as described in Fig. 1. In contrast, in response to TGF-β stimulation, Smad3 is phosphorylated by the TGF-β type I receptor and translocated into the nucleus, where p300/CREB-binding protein acetylates Smad3. Acetylation of Smad3 increases its DNA binding ability for the COL1A2 promoter. Thus, TGF-β coordinately regulates DNA binding activity of transcriptional activator “Smad3” and the repressor “Fli1”, leading to increased extracellular matrix production.

Fig. 3

The impact of Fli1 deficiency on dermal fibrosis in SSc. Fli1 deficiency due to an epigenetic mechanism in dermal fibroblasts results in the upregulation of type I collagen, CTGF/CCN2, and α-SMA, and the downregulation of MMP-1. Fli1 deficiency activates dermal fibroblasts in vivo in two distinct animal models, where the collagen fibers have an altered ultrastructure similar to that in SSc. To develop dermal fibrosis characteristic of SSc, some additional factors may be required.

Fig. 4

The impact of Fli1 deficiency on SSc vasculopathy. Fli1 deficiency due to an epigenetic mechanism in endothelial cells results in the downregulation of VE-cadherin, PECAM-1, PDGF-B, and S1P₁, and the upregulation of MMP-9. Endothelial cell-specific Fli1 knockout mice develop capillary dilation, vascular fragility, and arteriole stenosis, which are the histopathologic features of SSc vasculopathy. To develop the clinical symptoms of SSc vasculopathy, some additional factors may be required.

Fig. 5

Imatinib increases the DNA binding ability and protein stability of Fli1 in the context of dermal fibrobasts. Upon TGF-β stimulation, c-Abl and PKC-d are sequentially activated and Fli1 loses its inhibitory effect on the COL1A2 promoter through the phosphorylation-acetylation cascade. Imatinib inhibits c-Abl tyrosine kinase activity and subsequently increases the DNA binding and protein stability of Fli1 by blocking the phosphorylation-acetylation cascade.

Fig. 6

A new therapeutic strategy for SSc by targeting the transcription factor Fli1. A certain set of genetic factors, including Fli1 deficiency, may be required for the development of SSc. The reversal of Fli1 expression by tyrosine kinase inhibitors may be a promising therapeutic strategy. Combination treatment of imatinib with macrolides, which block the inhibitory effect of α1-acid glycoprotein for imatinib, would be another therapeutic option for SSc.