CD4 + Th cells play an important role in the development of rheumatoid arthritis (RA) by regulating adaptive immune response. As major subsets of CD4 + Th cells, Th17 cells can produce a large number of hallmark cytokines such as IL-17A and IL-17F, which participate in host defense and immune homeostasis. However, increasing researches have shown that Th17 cells are unstable and exhibit a certain degree of plasticity, which aggravates their pathogenicity. Furthermore, the plasticity and pathogenicity of Th17 cells are closely related with the disease activity in RA. In this paper, the characteristics including phenotype, differentiation, plasticity, and pathogenicity of Th17 cells in RA will be systematically summarized. This will contribute to clarify the immunologic mechanism of RA and further provide a novel strategy for the clinical treatment of autoimmune diseases. K E Y W O R D S pathogenicity, plasticity, rheumatoid arthritis, Th17 cells 1

Patients with rheumatoid arthritis (RA) suffer from pain, which is associated with inflammation, peripheral and central pain processing, and joint structure damage. The aim of the present study was to investigate a key microRNA (miR) and its target genes that are involved in the pain responses of RA, and to clarify the mechanism of pain regulation. Collagen-induced arthritis (CIA) was induced in DBA/1 and C57BL/6 mice. The paw swelling, mechanical withdrawal threshold (MWT), thermal withdrawal latency (TWL), and expression levels of tumor necrosis factor (TNF)-α and prostaglandin (PG)E2 in the sera were investigated. Decreased MWT and TWL, and increased TNF-α and PGE2, in the CIA model group were observed in DBA/1 and C57BL/6 mice. DBA/1 mice exhibited greater hyperalgesia and higher levels of inflammatory mediators. miR-143-3p expression in the blood and the dorsal root ganglion (DRG) were detected, and low miR-143-3p expression was demonstrated in the blood and DRG tissue of CIA mice. The target genes of miR-143 were predicted and analyzed. A total of 1,305 genes were predicted and 55 pain-associated genes were obtained. Prostaglandin-endoperoxide synthase 2 (Ptgs2), MAS related GPR family member E (Mrgpre), prostaglandin D2 receptor and Tnf were selected as target genes of miR-143. DRG cells were cultured and transfected with miR-143-3p inhibitor or mimic. The expression of Mrgpre, Ptgs2 and Tnf was significantly inhibited following miR-143-3p mimic transfection, while the expression of Mrgpre, Ptgs2 and Tnf was increased following inhibitor transfection. Additionally, the expression of pain-associated genes in the DRG of mice was investigated and the expression of Ptgs2, Mrgpre and Tnf in the DRG of CIA mice was also significantly upregulated. These results revealed that CIA mice exhibited marked hyperalgesia and high levels of inflammatory pain mediators. Low expression of miR-143-3p negatively regulated the pain-associated target genes, including Mrgpre, Ptgs2 and Tnf, thereby affecting chronic inflammatory pain and neuropathic pain in RA.

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Rheumatoid arthritis (RA) is a common chronic systemic autoimmune disease. Recent studies show that gut flora plays an important role in regulating the systemic immune response, and gut dysbacteria are linked with systemic chronic inflammation in the development of RA. Our previous results found that Qingluo Tongbi decoction (QLT) can treat RA effectively. The present study explored the effect of QLT on gut flora in an adjuvant-induced arthritis (AA) rat model. Thirty rats were divided randomly into three groups: a control group, a model group, and a treatment group (n = 10 per group). The rats in the model group were injected with complete Freund’s adjuvant (FCA), while the treatment group received FCA combined with QLT treatment. After 27 days, the gut flora was profiled by 16S rRNA gene sequencing. The levels of cadherin-11, IL-17α, TLR2, and TLR4 proteins in the synovial tissues were detected by western blotting (WB). The results showed that QLT treatment significantly inhibited raw swelling during the 15–27 d period compared with the model group. QLT treatment reversed the ten altered bacterial genera in the model group, and three families (Lachnospiraceae, Eubacteriaceae, and Leuconostocaceae) were closely related to QLT treatment based on linear discriminant analysis (LDA). Functional prediction showed seven types of predicted functions were related to the QLT treatment, and WB results showed that QLT treatment reversed the increased expression levels of cadherin-11, IL-17α, TLR2, and TLR4 in synovial tissues significantly. The expression levels of cadherin-11, IL-17α, and TLR2 correlated negatively with the abundance of Staphylococcus and Candidatus_Saccharimonas. Therefore, RA development was related to gut dysbiosis, and QLT effectively ameliorated RA with decreased inflammatory responses regulated by the gut flora.

Purpose Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease, and Th17 cells are key factors in the pathogenesis of human inflammatory conditions, such as RA. Catalpol (CAT), a component in Rehmanniae Radix (RR), has been found to regulate human immunity. However, the effects of CAT on Th17 cell differentiation and improvement of RA are not clear. Materials and Methods Collagen-induced arthritis (CIA) mice were constructed to detect the effects of CAT on arthritis and Th17 cells. The effect of CAT on Th17 differentiation was evaluated with let-7g-5p transfection experiments. Flow cytometry was used to detect the proportion of Th17 cells after CAT treatment. Levels of interleukin-17 and RORγt were assessed by qRT-PCR and enzyme-linked immunosorbent assay. The expression of signal transducer and activator of transcription 3 (STAT3) was determined by qRT-PCR and Western blot. Results We found that the proportion of Th17 cells was negatively associated with let-7g-5p expression in CIA mice. In in vitro experiments, CAT suppressed traditional differentiation of Th17 cells. Simultaneously, CAT significantly decreased Tregs-to-Th17 cells transdifferentiation. Our results demonstrated that CAT inhibited Tregs-to-Th17 cells transdifferentiation by up-regulating let-7g-5p and that the suppressive effect of CAT on traditional differentiation of Th17 cells is not related with let-7-5p. Conclusion Our data indicate that CAT may be a potential modulator of Tregs-to-Th17 cells transdifferentiation by up-regulating let-7g-5p to reduce the expression of STAT3. These results provide new directions for research into RA treatment.

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