Ontology and Function of Fibroblast-Like and Macrophage-Like Synoviocytes: How Do They Talk to Each Other and Can They Be Targeted for Rheumatoid Arthritis Therapy?

Abstract

Fibroblast-like synoviocytes (FLS) and macrophage-like synoviocytes (MLS) are the two main cellular components of the synovium. It has been widely reported that FLS and MLS play essential roles in the joint pathology of rheumatoid arthritis (RA). Although various studies have analyzed both human and animal tissues and have shown that both cell types are involved in different stages of RA, ontology, and specific functions of both cell populations and their interactions are not well understood. In this review, we will summarize recent research on FLS and MLS in RA and focus on the development and function of two predominant synovial cell types. In addition, we will discuss the communication between FLS or MLS and highlight potential treatments for RA that involve synoviocytes.

Keywords: fibroblast-like synoviocytes; macrophage-like synoviocytes; ontology; rheumatoid arthritis; synovium; treatment.

Figure 1

Speculative ontogeny of fibroblast-like synoviocytes (FLS) and macrophage-like synoviocytes (MLS). Macrophages from different organs/tissues are derived from embryonic stem cells (primitive and definitive hematopoiesis) or circulating monocytes (22). During murine embryogenesis, primitive hematopoiesis is firstly detected in blood islands of the yolk sac at around E7.5, which followed by definitive hematopoiesis in aorta-gonad-mesonephros (AGM) regions, then shifts to the fetal liver, spleen, and bone marrow. MLS most certainly are derived from embryonic precursor cells but the detailed ontogeny is still elusive. FLS may originate from Gdf5 + mesenchymal cells (E7.5, Day 7.5 at embryonic stage; E9.0, Day 9 at embryonic stage; E11.0, Day 11 at embryonic stage; E19.5, Day 19.5 at embryonic stage).

Figure 2

The roles of FLS in RA. FLS are involved in many pathological aspects of RA by promoting synovitis, pannus growth, and cartilage/bone destruction. Abbreviations: FLS, fibroblast-like synoviocytes; TNF-α, tumor necrosis factor α; IL-1, interleukin 1; VEGF, vascular endothelial growth factor; TGF-β, transforming growth factor β; PG, prostaglandin; IFN, interferon; GM-CSF, granulocyte-macrophage colony-stimulating factor; MMPs, matrix metalloproteinases; RANKL, receptor activator of nuclear factor kappa-B ligand; RA, rheumatoid arthritis.

Figure 3

The roles of MLS in RA. The three main effects of MLS in RA are mediated by cytokines secretion: (1) FLS activation, (2) recruitment of neutrophil/monoctes, and (3) T cells polarization. MLS are also affected by direct cell contact or indirect cytokine production by FLS, T cells, and B cells (autoantibody). In addition, in a serum-induced arthritis mouse, circulation recruited Ly6C⁻ monocytes limits development of arthritis mice and promotes the switch from M1 to M2 in the arthritis joint. Abbreviations: TNF, tumor necrosis factor; IL-1β, interleukin 1β; IL-8, interleukin 8; IL-23, interleukin 23; M-CSF, macrophage colony-stimulating factor; IFN- γ, interferon γ; CCL2, monocyte chemoattractant protein 1; T_H1, type 1T helper cells; T_H17, type 17 helper cells; MSL, macrophage-like synoviocytes; FSL, fibroblast-like synoviocytes; RA, rheumatoid arthritis.

Figure 4

The interaction between FLS and MLS in RA. FLS and MLS cross talk through secreted cytokines and MAPK pathway. FLS and MLS mutually activate via cytokines production; in addition, the pro-inflammatory and anti-inflammatory contest highlights the important role of the interaction between MLS and FLS via MAPK pathway in RA. Abbreviations: MAPK, mitogen-activated protein kinase; TAK1, TGF-beta activated kinase 1; MKK3, MAP kinase kinase 3; MKK6, MAP kinase kinase 6; MKK7, MAP kinase kinase 7; JNK, c-Jun N-terminal kinases; AP-1, APETALA 1; FOS, FBJ murine osteosarcoma viral oncogene homolog; STAT1, signal transducer and activator of transcription 1; CREB, cAMP responsive element binding protein 1; ERK, extracellular signal-regulated kinase; MSL, macrophage-like synoviocytes; FSL, fibroblast-like synoviocytes; RA, rheumatoid arthritis.

Figure 5

The current experimental and clinical FLS- and MLS-targeting treatments of RA. (1) Using of immune-modifying microparticles (polystyrene, micro-diamonds, or biodegradable poly-microparticles) to remove circulating monocytes or prevent the recruitment of monocytes into joints; (2) DMARDs to inhibit FLS or MLS secreted pro-inflammatory cytokines; (3) TNF-α monoclonal antibodies and TNF receptor 2–IgG1 fusion protein to specifically repress TNF-α-induced inflammation; (4) IL-6 antibodies to specifically repress IL-6-induced inflammation; (5) agents that targeting GM-CSF/GM-CSF-R/IRF-5 regulatory axis in MLS; (6) CDH11 antibody (FLS); (7) inhibitory agents to target JNK1, MKK7, and MAP3K7 in FLS and MLS; (8) CD64 antibody (FLS). Abbreviations: DMARDs, disease-modifying anti-rheumatic drugs; CD64, complement component 64; RA, rheumatoid arthritis; FLS, fibroblast-like synoviocytes; MSL, macrophage-like synoviocytes; CDH11, cadherin-11.