Abstract
Rheumatoid arthritis (RA) represents the consequence of an immune response of the body's immune system attacking healthy cells. This chronic inflammatory disorder has complicated pathogenesis. Traditional Chinese medicine (TCM) is well recognized as an effective therapy in treating RA and has been widely applied for centuries. Wu-Teng-Gao (WTG) is used as a representative natural herb formula in RA treatment in China, while its mechanisms are to be fully clarified. The present study attempted to explore mechanisms of WTG on RA treatment in a network pharmacological approach and verified using experiments in vitro. Following the establishment of a rat model of collagen-induced arthritis (CIA), WTG was applied externally on the metapedes of rats. HE staining was subsequently performed to visualize the pathological changes of synovium and bone. Simultaneously, flow cytometry was conducted to detect the cell ratio of T helper 17 (Th17) and Regulatory T cells (Treg) in splenic lymphocytes. Additionally, ELISA, qRT-PCR, and Western blot assays were adopted to determine expressions of RA-related factors in joints and serum. Results of network pharmacological analysis suggested that Th17 cell differentiation might serve as a potential signaling pathway of WTG therapy for RA. Animal experiments demonstrated that WTG ameliorated the articular inflammation and effectively inhibited the destruction of articular cartilage, and decreased Th17 and Treg cell ratios in CIA rats. Furthermore, WTG also greatly suppressed relevant levels of inflammatory cytokines (IL-17, TNF-α, IL-1, and IL-6) and RNAKL, whereas it elevated expressions of anti-inflammatory cytokines IL-10 and TGF-β. Our results confirmed that WTG might improve the imbalance of Th17/Treg cells in CIA animals through differentiation regulation, thus alleviating joint inflammation and bone destruction.
Highlights
Rheumatoid Arthritis (RA) has been well recognized as a systemic and chronic autoimmune disorder. e principal characteristics include the proliferation of synovial cells, infiltration of inflammatory cells, as well as destruction in articular cartilage and bones, resulting in joint deformity and disability [1]. e RA pathogenesis is intricate and unclear, which can be triggered by genetic factors, environmental factors, and aberrant immune systems [2]
As one subset of T cells [3], 17 cells play an essential role in proinflammation, and when in excess, such cells contribute to autoimmunity and tissue damage. e other subset of Tcells is Treg cells, which are antagonistic, and once they fail, the same diseases occur [3]. e 17/Treg ratio is lower in healthy control than that of RA patients, especially the active RA patients [4]. 17/IL-17 axis is of great significance in local inflammation and bone destruction of RA joints [5, 6]
Compared with the blank group, Treg cells were markedly elevated in the model group, whereas those in the WTG, IL-17 blocker, and diclofenac diethylamine emulgel (DDE) groups were increased markedly compared with the model group (Figure 3(b)). e ratio of 17/Treg cells in the model group was significantly increased compared with the blank group
Summary
Rheumatoid Arthritis (RA) has been well recognized as a systemic and chronic autoimmune disorder. e principal characteristics include the proliferation of synovial cells, infiltration of inflammatory cells, as well as destruction in articular cartilage and bones, resulting in joint deformity and disability [1]. e RA pathogenesis is intricate and unclear, which can be triggered by genetic factors, environmental factors, and aberrant immune systems [2]. Exosomes contain multiple proteins and nucleic acids, which are involved in T cell activation, antigen expression, intracellular signal transduction, inflammatory response, bone destruction, microvascular dysplasia, and other aspects. Following the principles of TCM theory, dampness and cold elimination and blood circulation promotion contribute to treating severe RA [13]. E current drug administration of RA treatment includes steroidal and non-steroidal anti-inflammatory medication, disease-modifying antirheumatic drugs, and biological preparations in clinical practice [14]. A meta-analysis has indicated that the treatment protocols that integrated TCM and Western medicines can achieve both effective and satisfactory results in treating RA [16]. TCM can realize the overall regulation of body functions through multifaceted and multi-target mechanisms, and it produces a remarkable curative effect on the treatment of RA [11]. The underlying mechanism by which TCM helps to alleviate RA remains unknown, thereby hindering its further clinical application
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