Abstract
Systemic sclerosis (SSc) is an autoimmune disease with fibrosis of the skin and internal organs and vascular alterations. Dysregulations in the oxidant/antioxidant balance are known to be a major factor in the pathogenesis of the disease. Indeed, reactive oxygen species (ROS) trigger neoepitopes leading to a breach of immune tolerance and autoimmune responses, activate fibroblasts to proliferate and to produce excess of type I collagen. ROS also alter endothelial cells leading to vascular dysfunction. Glutathione (GSH) is the most potent antioxidant system in eukaryotic cells. Numerous studies have reported a defect in GSH in SSc animal models and humans, but the origin of this defect remains unknown. The transcription factor NRF2 is a key player in the antioxidant defense, as it can induce the transcription of antioxidant and cytoprotective genes, including GSH, through its interaction with the antioxidant response elements. In this work, we investigated whether NRF2 could be implicated in the pathogenesis of SSc, and if this pathway could represent a new therapeutic target in this orphan disease with no curative medicine. Skin biopsies from 11 patients and 10 controls were harvested, and skin fibroblasts were extracted. Experimental SSc was induced both in BALB/c and in nrf2−/− mice by daily intradermal injections of hypochloric acid. In addition, diseased BALB/c mice were treated with an nrf2 agonist, dimethyl fumarate, or placebo. A drop in nrf2 and target genes mRNA levels was observed in skin fibroblasts of SSc patients compared to controls. Moreover, the nrf2 pathway is also downregulated in skins and lungs of SSc mice. In addition, we observed that nrf2−/− mice have a more severe form of SSc with increased fibrosis and inflammation compared to wild-type SSc mice. Diseased mice treated with the nrf2 agonist dimethyl fumarate (DMF) exhibited reduced fibrosis and immune activation compared to untreated mice. The ex vivo treatment of skin fibroblasts from SSc mice with DMF restores GSH intracellular content, decreases ROS production and cell proliferation. These results suggest that the nrf2 pathway is highly dysregulated in human and SSc mice with deleterious consequences on fibrosis and inflammation and that Nrf2 modulation represents a therapeutic target in SSc.
Highlights
Systemic sclerosis (SSc) is a rare and severe connective tissue disorder characterized by progressive fibrosis of the skin and visceral organs due to excessive collagen deposition, vasculopathy, and autoimmunity
As reactive oxygen species (ROS) metabolism is impaired in the skin of SSc patients, we first investigated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in fibroblasts extracted from the skin of patients
We analyzed the mRNA expression levels of nrf2 and its main target genes involved in the regulation of ROS production [heme oxygenase-1 (HO-1), glutamate cysteine ligase (GCL), and thioredoxin (TRX)] by quantitative RT-PCR in fibroblasts extracted from skin biopsies from SSc patients and healthy controls
Summary
Systemic sclerosis (SSc) is a rare and severe connective tissue disorder characterized by progressive fibrosis of the skin and visceral organs due to excessive collagen deposition, vasculopathy, and autoimmunity. Antioxidant defenses appear to be crucial in SSc development in regulating excessive ROS production, and play a key role in the pathogenesis of the disease [11,12,13]. When ROS overcomes the endogenous antioxidant capacity, Keap 1 releases NRF2 which translocates into the nucleus where it binds the antioxidant response elements in association with other transcription factors and accessory proteins. This event causes the transcriptional activation of major key antioxidants and cytoprotective proteins and enzymes responsible, among others, of glutathione (GSH) synthesis. We show that the nrf pathway is dysregulated in patients and in mice with SSc, and report a more severe form of SSc in Nrf2−/− mice along with the therapeutic properties of the nrf agonist DMF
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