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Decreased expression of microRNA-21 correlates with the imbalance of Th17 and Treg cells in patients with rheumatoid arthritis.

ABSTRACT: The imbalance of Th17/Treg cell populations has been suggested to be involved in the regulation of rheumatoid arthritis (RA) pathogenesis; however, the mechanism behind this phenomenon remains unclear. Recent studies have shown how microRNAs (miRNAs) are important regulators of immune responses and are involved in the development of a variety of inflammatory diseases, including RA. In this study, we demonstrated that the frequencies of CD3(+) CD4(+) IL-17(+) Th17 cells were significantly higher, and CD4(+) CD25(+) FOXP3(+) Treg cells significantly lower in peripheral blood mononuclear cells from RA patients. Detection of cytokines from RA patients revealed an elevated panel of pro-inflammatory cytokines, including IL-17, IL-6, IL-1?, TNF-? and IL-22, which carry the inflammatory signature of RA and are crucial in the differentiation and maintenance of pathogenic Th17 cells and dysfunction of Treg cells. However, the level of miR-21 was significantly lower in RA patients, accompanied by the increase in STAT3 expression and activation, and decrease in STAT5/pSTAT5 protein and Foxp3 mRNA levels. Furthermore, lipopolysaccharide stimulation up-regulated miR-21 expression from healthy controls, but down-regulated miR-21 expression from RA patients. Therefore, we speculate that miR-21 may be part of a negative feedback loop in the normal setting. However, miR-21 levels decrease significantly in RA patients, suggesting that this feedback loop is dysregulated and may contribute to the imbalance of Th17 and Treg cells. MiR-21 may thus serve as a novel regulator in T-cell differentiation and homoeostasis, and provides a new therapeutic target for the treatment of RA.

SUBMITTER: Dong L

PROVIDER: S-EPMC4224555 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Decreased expression of microRNA-21 correlates with the imbalance of Th17 and Treg cells in patients with rheumatoid arthritis.

Dong Liyang L Wang Xuefeng X Tan Jun J Li Hao H Qian Wei W Chen Jianguo J Chen Qiaoyun Q Wang Jun J Xu Wenlin W Tao Caihua C Wang Shengjun S

Journal of cellular and molecular medicine 20140828 11

The imbalance of Th17/Treg cell populations has been suggested to be involved in the regulation of rheumatoid arthritis (RA) pathogenesis; however, the mechanism behind this phenomenon remains unclear. Recent studies have shown how microRNAs (miRNAs) are important regulators of immune responses and are involved in the development of a variety of inflammatory diseases, including RA. In this study, we demonstrated that the frequencies of CD3(+) CD4(+) IL-17(+) Th17 cells were significantly higher, ...[more]

PMID: 25164131

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Project description:IntroductionRheumatoid arthritis (RA) is a chronic inflammatory disease involving a variety of immune cells, including adaptive T and B cells and innate lymphoid cells (ILCs). Understanding the pathogenic role of these immune cells in RA provides new insights into the intervention and treatment of RA.MethodsA total of 86 patients with RA (RA group) and 50 healthy controls (HC) were included in the study. The immune cells of CD4+, CD19+ B, NK, Th17, Treg, ILCs, and their subsets (i.e., ILC1s, ILC2s, and ILC3s) were characterized in peripheral blood mononuclear cells by flow cytometry. Cytokines (i.e., IFN-γ, IL-4, IL-10, IL-17A, IL-22, and IL-33) in sera were detected using ELISA. The above immune cells and cytokines were analyzed in patients with different disease activity status and positive ( +) or negative ( -) rheumatoid factor (RF)/anti-citrullinated protein antibodies (ACPA).ResultsPatients with RA had higher percentages of CD4+ T, CD19+ B, Th17, ILC2s, and ILC3s and lower percentages of Treg and ILC1s than HC. Patients with RA had elevated levels of IFN-γ, IL-4, IL-17A, and IL-22 and decreased level of IL-10. Compared with HC, patients with high disease activity had higher percentages of Th17, ILC2s, and ILC3s; lower percentages of ILC1s; and lower level of IL-10. The percentage of Treg cells in remission, low, moderate, and high disease activities decreased, whereas the level of IL-17A increased compared with HC. Furthermore, RF+ or ACPA+ patients exhibited elevated percentages of CD19+ B, ILC2s, and ILC3s and had decreased percentage of ILC1s and Treg cells than HC. The percentage of Th17 cells increased in RF-/ACPA- and RF+/ACPA+ patients. However, the above immune cells between RF or ACPA positive and negative patients were not significantly different.ConclusionTh17, Treg, and ILC subset dysregulations are present in patients with RA but may not be associated with conventionally defined seropositive RF and ACPA. Key Points • Th17, Treg, and ILC subset dysregulations are present in patients with RA but may reflect inflammation rather than specific diseases and stages. • No difference for the distribution of Th17, Treg, and ILC subsets between RF+ and RF- patients and between ACPA+ and ACPA- patients. The screening spectrum of RF and ACPA serology should be expanded to elucidate the role of immune cells in RA pathogenesis.

Project description:BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease of which the pathogenetic mechanisms are not fully understood. Semaphorin3A (Sema3A) has an immune regulatory role. Neuropilin1 (NRP1), the primary receptor for Sema3A, is also a receptor for vascular endothelial growth factor 165 (VEGF 165). It has been shown that Sema3A competitively antagonizes VEGF 165 signaling. This study investigated whether Sema3A is expressed in synovial tissues, and is associated with disease activity and the histological features of synovial tissues from RA patients. METHODS: Human synovial tissues samples were obtained from RA and osteoarthritis (OA) patients. Disease activity of RA patients was calculated using the 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP). The histological features of RA synovial tissues were evaluated using Rooney's inflammation scoring system. The localization of Sema3A, VEGF 165 and NRP1 positive cells was immunohistochemically determined in synovial tissues. Expression levels of Sema3A, VEGF-A and NRP1 mRNA were determined using quantitative real-time polymerase chain reaction (qPCR). RESULTS: In OA specimens, Sema3A, VEGF 165 and NRP1 proteins were expressed in the synovial lining and inflammatory cells beneath the lining. Immunohistochemistry revealed the protein expression of Sema3A in synovial lining cells was decreased in RA tissues compared with OA samples. qPCR analysis demonstrated a significant reduction of Sema3A mRNA levels in RA synovial tissue samples than in OA and a significant correlation of the ratio of Sema3A/VEGF-A mRNA expression levels with DAS28-CRP (R = -0.449, p = 0.013). Sema3A mRNA levels also correlated with Rooney's inflammation score, especially in perivascular infiltrates of lymphocytes (R = -0.506, p = 0.004), focal aggregates of lymphocytes (R = -0.501, p = 0.005) and diffuse infiltrates of lymphocytes (R = -0.536, p = 0.002). CONCLUSIONS: Reduction of Sema3A expression in RA synovial tissues may contribute to pathogenesis of RA.

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Decreased expression of microRNA-21 correlates with the imbalance of Th17 and Treg cells in patients with rheumatoid arthritis.

Publications

Decreased expression of microRNA-21 correlates with the imbalance of Th17 and Treg cells in patients with rheumatoid arthritis.

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