Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis

Abstract

Systemic sclerosis (SSc) is manifested by fibrosis, vasculopathy and immune dysregulation. So far, a unifying hypothesis underpinning these pathological events remains unknown. Given that SSc is a multifactorial disease caused by both genetic and environmental factors, we focus on the two transcription factors, which modulate the fibrotic reaction and are epigenetically suppressed in SSc dermal fibroblasts, Friend leukemia integration 1 (Fli1) and Krüppel-like factor 5 (KLF5). In addition to Fli1 silencing-dependent collagen induction, simultaneous knockdown of Fli1 and KLF5 synergistically enhances expression of connective tissue growth factor. Notably, mice with double heterozygous deficiency of Klf5 and Fli1 mimicking the epigenetic phenotype of SSc skin spontaneously recapitulate all the three features of SSc, including fibrosis and vasculopathy of the skin and lung, B cell activation, and autoantibody production. These studies implicate the epigenetic downregulation of Fli1 and KLF5 as a central event triggering the pathogenic triad of SSc.

Vasculopathy in scleroderma

“…Under this situation, a new genetic animal model of SSc, double heterozygous mice for Klf5 and Fli1 genes, has been established. This new SSc model is novel in that immune abnormalities, vasculopathy, and tissue fibrosis spontaneously and sequentially occur in this order, which is reminiscent of the natural disease course of SSc [91]. Given that KLF5 and FLI1 genes are epigenetically suppressed in SSc dermal fibroblasts [17,91], this animal model supports the notion that environmental factors play a pivotal role in the development of SSc in individuals highly predisposed by genetic factors [3].…”

“…Furthermore, structural abnormalities of vasculature such as stenosis of arterioles and bushy capillaries appear in the skin. Moreover, pulmonary vascular changes corresponding to PAH and pulmonary veno-occlusive disease are also evident [91]. Therefore, Klf5 +/− ;Fli1 +/− mice develop both destructive vasculopathy and proliferative obliterative vasculopathy characteristic of SSc.…”

“…Given that vascular network alterations of Klf5 +/− mice and Fli1 +/− mice are normal and modest, respectively, simultaneous haploinsufficiency is required for the development of far more significant vascular abnormalities. Although the molecular mechanism underlying vasculopathy in Klf5 +/− ;Fli1 +/− mice still remains unknown, Fli1 deficiencydependent activation of pro-angiogenic signaling and Klf5 deficiency-mediated connective tissue growth factor (CTGF) induction may contribute to this process [40,91]. Endothelial cell-specific Fli1 knockout mice mimic vascular disintegrity of SSc which is characterized by reduced interaction between endothelial cells and PCs/vSMCs due to the activation of proangiogenic gene program [40].…”

Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis

“…Thus, IRF5, perhaps constantly but weakly activated in these mice, may influence extracellular matrix homeostasis by regulating fibrosis-and fibrillogenesis-associated gene expression in dermal fibroblasts (see below). It is worth noting that, except for the Dcn gene, these gene-expression profiles are contrary to those of SSc (18).…”

Identification of periplakin as a major regulator of lung injury and repair in mice

“…Klf5 is required for perinatal lung maturation and the expression of many genes essential for lung function (27). Inhibition of Klf5 expression has been shown to be a master event in the development of skin and lung fibrosis in mice (28). Egr2 is a functionally distinct transcription factor that is both necessary and sufficient for TGF-β-induced profibrotic responses, and it is aberrantly expressed in lesional tissue in systemic sclerosis and in a murine model of scleroderma (29).…”