Myeloid Fli1 deficiency induces tissue fibrosis, vasculopathy, and immune abnormalities recapitulating systemic sclerosis

Abstract

Systemic sclerosis (SSc) is a multisystem chronic disease characterized by immune abnormalities, vasculopathy, and tissue fibrosis. In SSc lesional skin, transcription factor Friend leukemia virus integration 1 (Fli1) is constitutively down-regulated in various cell types, especially by an epigenetic mechanism in dermal fibroblasts, and Fli1 deficiency in dermal fibroblasts and endothelial cells induces an SSc-like phenotype in each cell type. However, it has still remained to be elucidated whether Fli1 deficiency in immune cells has an impact on the pathogenesis of SSc. As a part of studies to address this issue, we focused our interests on myeloid cells in this study. We generated myeloid cell-specific Fli1 deficient (Fli1 Mye-KO) mice (LysM-Cre+/−Fli1flox/flox) and examined the phenotypic changes in these mice. Fli1 Mye-KO mice showed increased dermal thickness and collagen production through activation of dermal fibroblasts. As for vasculopathy, Fli1 Mye-KO mice showed stenosis, dilatation, and regression of dermal blood vessels as visualized by FITC-conjugated dextran injection. Increased permeability of dermal blood vessels was also confirmed by leakage of Evans blue dye into interstitial spaces in Fli1 Mye-KO mice. Histopathological analysis of the skin of Fli1 Mye-KO mice showed decreased pericyte coverage in dermal blood vessels, leading to endothelial hyperplasia, vascular dilatation, and decreased stability of blood vessels. Regarding immune dysfunction, Fli1 Mye-KO mice showed production of anti-nuclear antibodies. Thus, Fli1 deficiency in myeloid cells may contribute to the induction of three cardinal pathological features of SSc, including dermal fibrosis, vascular injury, and immune abnormalities.