Notoginsenoside R1 (NG-R1) Promoted Lymphatic Drainage Function to Ameliorating Rheumatoid Arthritis in TNF-Tg Mice by Suppressing NF-κB Signaling Pathway.

Danli Jiao,Yang Liu,Hao Xu,Qi Shi,Tong Hou,Xiaoyun Wang,Qiujuan Xing,Yongjun Wang,Qianqian Liang

doi:10.3389/fphar.2021.730579

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is primarily characterized by synovial inflammation. Our previous studies demonstrated that the lymphatic system is critical for the development and maintenance of RA disease, and sufficient lymph drainage helps to improve joint inflammation. In this study, we found that NG-R1, the main active component in the traditional Chinese medicinal herb Sanchi, activating lymphatic function can attenuate synovial inflammation. According to histopathological staining of ankle sections, NG-R1 significantly decreased the area of inflammation and reduced bone destruction of ankle joints in TNF-Tg mice. Near infrared-indocyanine green (NIR-ICG) lymphatic imaging system has shown that NG-R1 significantly improved the lymphatic drainage function. However, the molecular mechanism of its activity is not properly understood. Our in-depth study demonstrates that NG-R1 reduced the inflammatory cytokine production of lymphatic endothelial cells (LECs) stimulated by TNF-α, and the mechanism ameliorated the phosphorylation of IKKα/β and p65, and the translocation of p65 into the nucleus. In summary, this study proved that NG-R1 promoted lymphatic drainage function to ameliorating rheumatoid arthritis in TNF-Tg mice by suppressing NF-κB signaling pathway.

Highlights

Rheumatoid arthritis is a chronic systemic disease with autoimmune pathogenesis and systemic involvement, which is associated with the overexpression profile of many proinflammatory cytokines (Petrovska et al, 2021, 102797; Hosseinikhah et al, 2021)
As for arthritis symptoms assessment, we found that NG-R1 treatment group did significantly attenuate the degree of joint malformation and ankle circumference in TNF-Tg mice compared to the model group (Figures 1B,C)
To further confirm the anti-inflammatory effect of NG-R1 in TNF-Tg mice, we tested the expression of serum inflammatory factors in mice by ELISA Kit and found that NG-R1 could effectively inhibit the expression of serum inflammatory factors IL-6 and TNF-α (Figures 1E,F)

Summary

Introduction

Rheumatoid arthritis is a chronic systemic disease with autoimmune pathogenesis and systemic involvement, which is associated with the overexpression profile of many proinflammatory cytokines (Petrovska et al, 2021, 102797; Hosseinikhah et al, 2021). Long-term chronic inflammation will stimulate lymphatic endothelial cells (LECs) to release proinflammatory cytokines, which will accelerate the apoptosis of lymphatic smooth muscle cells (LSMCs) and inhibit their proliferation (Telinius and Hjortdal, 2019, 1777–1784, Liang et al, 2021, 58). This persistent inflammation leads to structural and functional of lymphatics abnormalities, lymphatic drainage dysfunction, and further aggravates the inflammation of the joints (Deng et al, 2021, 2174; Liang et al, 2020, e12876). Most importantly, targeting lymphatics represents an innovative strategy for therapeutic intervention in RA

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Conclusion