It is still a clinical challenge to sustain the remission of rheumatoid arthritis (RA); thus, identifying more effective and safer agents for RA treatment remains an urgent demand. We investigated the anti-arthritic activity and potential mechanism of action of sodium Danshensu (SDSS), a structurally representative water-soluble derivative of Danshen, on collagen-induced arthritis (CIA) mice. Our results showed that paw edema, synovium hyperplasia, bone destruction, and the serum levels of both IL-1β and IL-6 were ameliorated by SDSS (40 mg/kg·d) in CIA mice. In addition, there was no difference between SDSS and methotrexate (MTX, 2 mg/kg·3d) treatment in the above indicators. Further mechanism studies illustrated that SDSS inhibited IL-1β secretion by downregulating the HIF-1α/STAT3/NLRP3 pathway in macrophages. On the other hand, HIF-1α accumulation and HIF-1α/STAT3/NLRP3 pathway activation by IOX4 stimulation reduced the therapeutic effect of SDSS. These findings demonstrate that SDSS displays anti-arthritic activity in CIA mice and prevents proinflammatory cytokines secretion in macrophages by suppressing the HIF-1α/STAT3/NLRP3 pathway.

Treg cells play an important role in the induction of autoimmune tolerance, and their ability of antigen recognition and regulation is determined by the receptor (TCR). TCR diversity determines the autoimmune responses in RA and is closely associated with autoimmune diseases prognosis and prevention. Previous studies have found that there is immunosenescence in RA, that is, the decrease of the number of naïve CD4 ⁺ T cells and the reduction of TCR repertoire diversity. High disease activity is an independent risk factor for RA. We speculate that high disease activity is related to immunosenescence—the decline of adaptive immune function and a chronic inflammation, but its biological mechanism is still unclear and needs to be further elucidated. In this study, high-throughput Immuno-Seq sequencing and flow cytometry were used to compare normal subjects and RA patients, as well as RA patients whose disease activity changed to clinical remission after standard treatment. It was found that high disease activity not only led to a decrease in the number of naïve Treg cells, but also led to a decrease in the diversity of Treg cell receptor repertoire, weakening their ability to recognize self-antigens and induce immune tolerance, leading to the occurrence and development of RA. Besides, these characteristics of the TCR repertoire, particularly the disease activity related clones, can potentially serve as biomarkers and provide novel insights for disease status and therapeutical targets in autoimmune diseases.