Two Main Cellular Components in Rheumatoid Arthritis: Communication Between T Cells and Fibroblast-Like Synoviocytes in the Joint Synovium

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that endangers the health of approximately 1% of the global population. Current RA medications on the market mainly include non-steroidal anti-inflammatory drugs, biological agents, and disease-modifying drugs. These drugs aim to inhibit the overactivated immune response or inflammation of RA, but they cannot cure RA. A better understanding of the pathogenesis of RA will provide a new understanding to search for RA targets and for drug development. The infiltration of T cells and hyper-proliferation of fibroblast-like synoviocytes (FLS) in the synovium of patients with RA are significantly upregulated. Furthermore, the abnormal activation of these two types of cells has been confirmed to promote development of the course of A by many studies. This article systematically summarizes the interactions between T cells and FLS in RA synovial tissues, including one-way/mutual regulation and direct/indirect regulation between the two. It further aims to investigate the pathogenesis of RA from the perspective of mutual regulation between T cells and FLS and to provide new insights into RA research.

Keywords: FLS; RA; T cells; cellular interaction; therapy.

Figure 1

RA-FLS indirectly promotes survival and chemotaxis of T cells in joint synovium of patients with RA via by producing various chemokines, including CD13, SDF1, VCAM1, IL15, TNF, and type I IFN. SDF, Stromal cell-derived factor; VCAM, Vascular cell adhesion molecule; VLA,Integrins alpha; CXCR, CXC motif chemokine receptor; IL, interleukin; JAK, Janus kinase; STAT, signal transducer and activator of transcription; TNF, tumor necrosis factor; IFN, interferon.

Figure 2

FLS regulates differentiation of CD4⁺ T cells in RA. P53 KD and EZH2 OE promote Th1 and Treg differentiation of T cells in RA synovium, respectively. FLS promotes Tfh differentiation of T cells via IL-6. FLS directly induces Th17 differentiation through cytokines, including CCL20, MRP8, IL-6, and IL-26, etc. KD, knockdown; OE, overexpression; Tfh, T follicular helper; CCL, C–C motif chemokine ligand; MRP, myeloid-related protein; TLR, Toll-like receptor; Cyr61, cysteine-rich protein 61; EZH, enhancer of zeste homolog; Treg, regulatory T cells.

Figure 3

T cells promote inflammatory phenotype of FLS in RA, mainly including proliferation, migration, invasion, and production of proinflammatory cytokines and destructive MMPs in joint synovium. (A) The indirect effects of Th17 cells on FLS in RA; (B) The indirect effects of Th1/Th2 cells on FLS in RA; (C) The indirect effects of other T cells on FLS in RA. GM-CSF, granulocyte-macrophage colony-stimulating factor; MMP, matrix metalloproteinase; RANKL, receptor activator of NF-κB ligand; TRAF, TNF receptor-associated factor; AP, activator protein; ICAM, intercellular adhesion molecule; MIF, migration inhibitory factor; ATAC, activation-induced, T cell-derived, and chemokine-related cytokine; Lptn, lymphotactin; FAK,focal adhesion kinase.

Figure 4

FLS directly regulate functions of T cells in RA.

Figure 5

T cells directly regulate FLS in RA. CII:type II collagen; FKN, Fractalkine; TSP, thrombospondin.

Figure 6

The mutual regulation of T cells and FLS in RA. CIA, collagen-induced arthritis; T_em: effector memory T; AIA, adjuvant-induced arthritis.