An orally-active adiponectin receptor agonist mitigates cutaneous fibrosis, inflammation and microvascular pathology in a murine model of systemic sclerosis

Takashi Yamashita,Shinichi Sato,Feng Fang,Ayumi Yoshizaki,Yoshihide Asano,Wen Hong,Takashi Taniguchi,Snezn Sodin-Semrl,Xingchun Zhou,Katja Lakota,John Varga

doi:10.1038/s41598-018-29901-w

Abstract

The hallmarks of systemic sclerosis (SSc) are autoimmunity, microangiopathy and fibrosis. Skin fibrosis is accompanied by attrition of the dermal white adipose tissue layer, and alterations in the levels and function of adiponectin. Since these findings potentially implicate adiponectin in the pathogenesis of SSc, we employed a novel pharmacological approach to augment adiponectin signaling using AdipoRon, an orally active adiponectin receptor agonist. Chronic treatment with AdipoRon significantly ameliorated bleomycin-induced dermal fibrosis in mice. AdipoRon attenuated fibroblast activation, adipocyte-to-myofibroblast transdifferentiation, Th2/Th17-skewed polarization of the immune response, vascular injury and endothelial-to-mesenchymal transition within the lesional skin. In vitro, AdipoRon abrogated profibrotic responses elicited by TGF-β in normal fibroblasts, and reversed the inherently-activated profibrotic phenotype of SSc fibroblasts. In view of these broadly beneficial effects on all three cardinal pathomechanisms underlying the clinical manifestations of SSc, pharmacological augmentation of adiponectin signaling might represent a novel strategy for the treatment of SSc.

Highlights

Systemic sclerosis (SSc) is a chronic multi-factorial disease characterized by early inflammation, followed by microangiopathy and fibrosis in the skin and internal organs[1]
The results showed a significant decrease in Tgfb[1] and Ctgf gene expression in mice treated with AdipoRon (Fig. 1d), which was confirmed by immunohistochemistry (Fig. 1e and Supplementary Table 1)
These findings indicate that chronic AdipoRon treatment exerts a potent anti-fibrotic effect in mice by attenuating myofibroblast transition, adipocyte-to-myofibroblast transdifferentiation, collagen accumulation and expression of key pro-fibrotic growth factors within the lesional skin

Summary

Introduction

Systemic sclerosis (SSc) is a chronic multi-factorial disease characterized by early inflammation, followed by microangiopathy and fibrosis in the skin and internal organs[1]. Recent studies have generated substantial evidence implicating deregulated adipocyte function and adipokine secretion as pathogenic factors in fibrosis and SSc. A pathologic hallmark of SSc is accumulation in the lesional tissue of activated myofibroblasts that are responsible for excessive extracellular matrix (ECM) deposition and tissue remodeling. Taken together with its potent pleiotropic biological activities, including anti-inflammatory and anti-fibrotic effects[26,27,28,29], deregulated adiponectin signaling is likely to have a role in SSc pathogenesis. The present studies sought to investigate the effects of AdipoRon in an experimental model of SSc that recapitulates inflammatory, vascular and fibrotic features of the human disease. The results indicate that AdipoRon treatment attenuated inflammation, microvascular injury and fibrosis in the skin, and abrogated TGF-β-mediated and constitutive activation of normal and SSc fibroblasts.

Methods

Results

Conclusion