Cytokines and miRNAs in the Pathogenesis of Rheumatoid Arthritis: A Review

Review Article

Austin Med Sci. 2021; 6(1): 1045.

Cytokines and miRNAs in the Pathogenesis of Rheumatoid Arthritis: A Review

Yu Z1#, Hu Y1#, Liu H2, Fan J1 and Liu W1*

¹Department of Orthopaedics, Affiliated Hospital 2 of Nantong University, Nantong, Jiangsu, China

²School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China

#Yu Z and Hu Y contributed equally to this work

*Corresponding author: Wei Liu, Department of Orthopaedics, Affiliated Hospital 2 of Nantong University, 6 Haierxiang Road, Nantong 226001, Jiangsu, China

Received: April 19, 2021; Accepted: May 08, 2021; Published: May 15, 2021


Rheumatoid Arthritis (RA) is a chronic autoimmune disease characterized by inflammatory synovial hyperplasia. The pathogenesis of RA may be related to heredity, infection and sex hormones. The initial stage of RA involves the activation of T cells. Immature CD4+ T cells differentiate into T helper (Th) cells and T regulatory (Treg) cells under antigen stimulation and cytokine signal transduction. Cytokines secreted by Th cells and Treg cells play crucial roles in the pathophysiology of RA. The cytokines can be roughly divided into proinflammatory cytokines, anti-inflammatory cytokines, and both pro- and antiinflammatory cytokines. The imbalance between pro-inflammatory cytokines and anti-inflammatory cytokines would lead to a variety of autoimmune diseases. The disease severity was significantly indicated by serum or plasma cytokine levels with RA patients. Many clinical trials have shown that anticytokine drugs are effective in treating RA. This article reviews the differentiation process of different Th cells and Treg cells, the roles of cytokines secreted by them in the pathogenesis of RA and how miRNAs mediate immune regulation in RA. By understanding the roles of cytokines and miRNAs in the pathogenesis of autoimmunity, it is necessary to develop potential anti-cytokine drugs and biomarkers/therapeutic targeted drugs through various ways in the treatment of RA.

Keywords: Rheumatoid arthritis; T helper cells; T regulatory cells; Proinflammatory cytokines; Anti-inflammatory cytokines; miRNA


RA: Rheumatoid Arthritis; Th cells: T helper cells; Treg cells: T regulatory cells; Foxp3: Forkhead Box Protein 3; IFN: Interferon; IL: Interleukin; T cells: T lymphocytes; APC: Antigen-Presenting Cells; MHC-II: Major Histocompatibility Complex-II; STAT: Signal Transducer and Activator of Transcription; IL-12R: IL-12 Receptor; CXCR: CXC Motif, Receptor; CCR: C-C Chemokine Receptor; IP10: IFN-γ-Inducible 10-kDa Protein; Mig: Monokine Induced by IFN-γ; I-TAC: IFN-Inducible T cell Alpha Chemoattractant; Smads: Smad Family Proteins; TGF-ß: Transforming Growth Factor-ß; RORγt: Retinoid-Related Orphan Receptor γt; IRF4: Interferon Regulatory Factor 4; nTregs: natural Tregs; iTregs: induced Tregs; TIGIT: T cell Ig and ITIM domain; CIA: Collagen-Induced Arthritis; G: Guanine; A: Adenine; MSCs: Mesenchymal Stem Cells; IL-6Ra: IL6-specific Receptor a; sIL-6R: Soluble IL-6R; CSIF: Cytokine Synthesis Inhibitory Factor; vIL-10: Viral IL-10; EBI3: Epstein-Barr virus-Induced Gene 3; EAE: Experimental Autoimmune Encephalomyelitis; PIAS3: Protein Inhibitor of STAT3; VEGF: Vascular Endothelial Growth Factor


Rheumatoid Arthritis (RA) is a chronic autoimmune disorder characterized by nonspecific inflammation of synovial membranes and joints. Accompanied by extraarticular organ involvement and serum rheumatoid factor positive, RA would lead to joint deformity and loss of function. Increasing with considerable morbidity and mortality worldwide, RA is affecting 0.5-1.0% of the general population [1]. A heavy economic pressure was brought and a social burden on the whole world by RA.

As a critical role in host defense, CD4+ T cells make major contributions to the generations of autoimmune and inflammatory diseases. Naive CD4+ T cells were differentiated into various forms of T helper (Th) cells and T regulatory (Treg) cells under such various conditions as antigenic stimulation and cytokine signaling. Since the discovery of the Th1/Th2 dichotomy by Robert Coffman and Timothy Mossman in 1986, many Th subsets were discovered. Each Th subset was found with a unique cytokine profile, functional properties and distinctively presumed roles in the autoimmune tissue pathology. Treg cells play an important role in regulating the immune response. Treg cells were lately discovered in regulating Forkhead box protein 3+ (Foxp3+) as key molecules. Another significant member of the CD4+ T cell subsets is Th17 cell; it plays a critical role in autoimmune diseases. In recent years, with the help of modern technology, the knowledge of Th17 cells was with tremendous development. Th17 cells also contribute to the pathogenesis of arthritis by modulating antibody function [2]. Manipulation of dysregulated miRNAs in vivo through miRNA delivery or inhibition offered a promise for new therapeutic strategies in treating rheumatic diseases [3].

CD4+ T cells & Th cells

In 1986, Robert Coffman and Timothy Mossman had a revolutionary discussion over two types of Th cells, Th1 and Th2 cells, based on the cytokine secreted by distinct CD4+ T cell subsets [4], Interferon-γ (IFN-γ) and interleukin-4 (IL-4), respectively [5]. In recent years, the classical Th1/Th2 models were hugely modified and the mechanisms of Th cell differentiation were deeply uncovered.

Originated from lymphoid cells of marrow, T lymphocytes (T cells) maturate in thymus under complicated and rigorous regulations. Exiting from thymus, matured T cells carry all the genetic components to recognize antigens and express CD4 or CD8 molecules. Exogenous antigens are ingested by Antigen-Presenting Cells (APC) through phagocytosis or pinocytosis to form phagosomes. Phagosome was fused with lysosomes to form phagolysosomes. Antigens are degraded into small molecular polypeptides by proteolytic enzymes in acidic environment of phagolysosomes, among which antigen peptides are immunogenic. After entering the Golgi apparatus, the Major Histocompatibility Complex-II (MHC-II) molecules synthesized in the endoplasmic reticulum are carried by secretory vesicles and fuse with phagolysosomes to form an antigen-peptide-MHC-II complex. The complex expressed on the surface of APC can be identified and bound by corresponding CD4+ T cells. Through a complex process of blast cell transformation, the activated T cells can undergo further differentiation to various subtypes of T cells and can express different combinations of immune response genes [6].

Th1 cells

Th1 cell differentiation is generally induced by IL-12 secreted from APCs. However, IFN-γ mRNA, and only modestly augments antigen-induced IFN-γ mRNA cannot be induced by IL-12 itself from Th1 cells [7]. IFN-γ and IL-12 cytokines activate signal transducer and activator of transcription 1 (STAT1) and STAT4 respectively to promote the expression of T-bet, IFN-γ and IL-12 receptor (IL-12R) ß2 [8-10]. T-bet, discovered as a novel protein belonging to the T box family by Szabo et al. in 2000 [11], is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells [9]. T-bet was served as a master regulator for Th1 cell differentiation [11]. The expression of T-bet resulted in Th1 cell development and the specific expression of IFN-γ [11] as well as IL-12Rß2. The production of IFN-γ and IFN-γ-STAT1-T-bet pathway construct a positive feedback loop. IFN-γ- STAT1-T-bet pathway was considered as the main mechanism of Th1 cell differentiation. It is worth mentioning that Lighvani et al. firstly found that the IFN-γ-STAT1-T-bet pathway serves as a powerful amplification mechanism in Th1 cell differentiation in vitro [12]. However, the IL-12-STAT4-T-bet pathway is critical both in vitro and in vivo to Th1 cell differentiation [13]. The differentiation and secretion processes of Th cells and Treg cells were illustrated in Figure 1.

Citation: Yu Z, Hu Y, Liu H, Fan J and Liu W. Cytokines and miRNAs in the Pathogenesis of Rheumatoid Arthritis: A Review. Austin Med Sci. 2021; 6(1): 1045.