Deficiency of NRF2 aggravates BLM-induced systemic sclerosis-associated fibrosis and inflammation in mice.

Abstract

BACKGROUND: Systemic sclerosis (SSc), also called scleroderma, is a chronic autoimmune connective tissue disorder characterized by fibrosis of the skin and internal organs and vasculopathy. Its pathogenesis involves abnormal activation of fibroblasts, inflammatory response and oxidative stress. Studies have shown that nuclear factor E2-related factor 2 (NRF2), as a key transcription factor regulating oxidative stress, not only affects the process of organ fibrosis, but also dynamically modulates the inflammatory response. Data from clinical studies showed that the remarkably abnormal expression of NRF2 at skin lesions in SSc patients suggested the pathological relevance between NRF2 and SSc. METHODS: Wild type (WT) mice and NRF2 Knockout (NRF2 KO) mice were subcutaneously injected with Bleomycin (BLM) as an SSc mouse model, and primary mouse fibroblasts were induced through BLM and HOas vitro model to investigate the role of NRF2 in the onset and progression of SSc. RESULTS: NRF2 deficiency exacerbated the BLM-induced skin hyperplasia and collagen deposition in mice, compared with the WT group. In addition, NRF2 deficiency significantly regulated the expression of the genes associated with skin fibrosis, inflammatory response and oxidative stress. CONCLUSION: NRF2 deficiency promotes fibrosis, inflammation and oxidative stress in SSc-like mice by activating JAK/STAT signaling pathway. Our research provides a new potential target and its underlying mechanisms for the clinical treatment of scleroderma.