Therapeutic mechanisms of polysaccharides in the management of rheumatoid arthritis: a comprehensive review

Abstract

Rheumatoid Arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and destruction of articular cartilage and bone, which seriously affects patients' quality of life. In recent years, with the in-depth research on natural medicines, the application of polysaccharides in the treatment of RA has gradually gained attention due to their unique bioactive components and diverse pharmacological effects. Polysaccharides were reported to exert anti-inflammatory, antioxidant, immunomodulatory, and protective effects on cartilage and bone tissues. This review briefly introduces RA, its etiology and pathogenesis, and the different sources and structures of polysaccharides. It focuses on the mechanisms of polysaccharides in the alleviation of RA, mainly through the modulation of immune cell function, inhibition of inflammation, regulation of gut microbiota, promotion of bone formation and repair, and influence on related pathways. The aim of this review is to summarize the polysaccharides and their mechanisms of action in the alleviation of RA, with a view to providing new ideas for the clinical treatment of RA.

Keywords: cytokines; immune cells; mechanism; polysaccharides; rheumatoid arthritis (RA).

Figure 1

(A) Number of polysaccharide- and RA-related papers obtained from the Web of Science core database from 2015 to 2024. (B) Keyword co-occurrence map of bibliographic data created using VOSviewer from 2015 to 2024. Specifically, this area remains underexplored from 2015 to 2024. In 2022, polysaccharides for RA were published to a near-decade high of 34 articles, and have remained at 25 articles in 2023 and 2024. Thus, research findings on polysaccharides for RA have been of interest.

Figure 2

RA can also involve internal organs other than joints. Specifically, this can manifest as interstitial lung lesions, rheumatoid nodules, skin ulcers, and neurologic, cardiac, and eye lesions.

Figure 3

The development of RA is the result of a combination of factors. Specifically, Immune Cells (mast cells, macrophages, T-cells and B-cells, Synoviocytes, SMs, FLS), Inflammatory Cytokines (TNF and IL-6), Environmental factors (Silica dust, Long-term smoking, Cold and humid environments Exposure to certain chemicals and Other Causes (Gut microbiota, Genetic predisposition, A variety of infections, General endocrine factors) jointly accelerated the development of RA.

Figure 4

Mechanism of action of polysaccharides to alleviate OA in mouse. Specifically, polysaccharides of different origins treat RA progression by modulating immune macrophages, inhibiting inflammatory factors, improving the gut microbiota and its metabolites, promoting cartilage and bone tissue repair, and modulating related pathways. Image created with BioRender.com, with permission.

Figure 5

Polysaccharides affect signaling pathways such as NF-κB, PI3K/AKT, JAK/STAT, and MAPK to improve RA. IL-1R (interleukin-1 receptor) is a key upstream initiator of the NF-κB signaling pathway activating NF-κB through the TRAF6-TAK1-IKK cascade reaction, a central driver of the inflammatory response. While TNFR initiates the PI3K/AKT signaling pathway, it can also lead to phosphorylated degradation of IκBα through activation of the IKK complex, which in turn releases and activates NF-κB transcription factors. In the JAK/STAT signaling pathway, cytokine binding to the receptor activates JAK, which in turn catalyzes STAT phosphorylation, and the phosphorylated STAT forms a dimer that enters the nucleus to regulate gene expression. In the MAPK (including JNK, ERK, and P38) signaling pathway, upstream growth factors bind to the receptor to phosphorylate SHC, recruiting GRB2 and SOS. SOS prompts activation by exchanging Ras-bound GDP for GTP. Activated Ras activates Raf1 (a MAP3K), MAP3K activates MEK1 (MAP2K), and MEK1 phosphorylates ERK1/2 (MAPK). ERK enters the nucleus and regulates gene expression, while JNK and P38 function through a similar cascade. Image created with BioRender.com, with permission.