Synovial tissue macrophages: friend or foe?

Abstract

Healthy synovial tissue includes a lining layer of synovial fibroblasts and macrophages. The influx of leucocytes during active rheumatoid arthritis (RA) includes monocytes that differentiate locally into proinflammatory macrophages, and these produce pathogenic tumour necrosis factor. During sustained remission, the synovial tissue macrophage numbers recede to normal. The constitutive presence of tissue macrophages in the lining layer of the synovial membrane in healthy donors and in patients with RA during remission suggests that this macrophage population may have a role in maintaining and reinstating synovial tissue homeostasis respectively. Recent appreciation of the different origins and functions of tissue-resident compared with monocyte-derived macrophages has improved the understanding of their relative involvement in organ homeostasis in mouse models of disease. In this review, informed by mouse models and human data, we describe the presence of different functional subpopulations of human synovial tissue macrophages and discuss their distinct contribution to joint homeostasis and chronic inflammation in RA.

Keywords: arthritis; inflammation; synovitis.

Figure 1

The role of synovial tissue macrophages in arthritis. (A) The mouse synovium contains major histocompatibility complex (MHC) class II negative (MHC-II⁻) tissue-resident macrophages that originate from prenatal precursors and have the capacity to proliferate. On induction of experimental arthritis, there is an influx of monocytes (Ly6C⁺or Ly6C⁻, depending of the nature of the induction) that differentiate into MHC class II positive (⁺) proinflammatory macrophages that mediate joint pathology. Resolution of arthritis is associated with a phenotypic change of the monocyte-derived macrophages from proinflammatory to anti-inflammatory, along with the contribution of tissue-resident macrophages. (B) In humans, the synovial membrane of healthy subjects and of patients with RA in sustained remission contain macrophages in the lining layer. Their origin and function are unknown. In patients with active arthritis, the CD14⁺ subpopulation of infiltrating monocytes contributes to the increased MHC-II⁺ proinflammatory macrophage pool in the inflamed synovium. Proinflammatory macrophages of patients with arthritis produce a broad range of inflammatory mediators, and their phenotype is maintained by the miR-155/SHIP-1 pathway. PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; RA, rheumatoid arthritis; SHIP-1, phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1; TLR, Toll-like receptors.

Figure 2

What is the tissue-specific function of synovial-resident macrophages? Tissue-specific functions of resident-tissue macrophages are induced by local cues. Their function in the synovium is unknown, but we can speculate by reference to other tissues. In the lung, for example, the differentiation of alveolar macrophages is driven by lung epithelial cell-derived GM-CSF, and recycling of surfactant is regulated by transcription factor PPARγ. Deficiency of alveolar macrophages, GM-CSF or PPARγ leads to pulmonary proteinosis. Spleen red pulp macrophages specialised in iron-recycling. This function is induced by heme derived from erythrocyte degradation and executed by BACH2 and SPIC. Selective deficiency of red pulp macrophages (deficiency of SPIC) leads to aberrant iron metabolism. Osteoclasts are bone macrophages that specialise in bone degradation. Their functional programme is induced by RANKL and executed by multiple transcription factors, including NFATC1. Deficiency in functional osteoclasts (RANKL^−/− or M-CSF^-−/−) leads to an increase in bone mass (osteopetrosis). Speculatively, in healthy joints, synovial tissue macrophages may specialise in recycling lubricin, the lubricating components of synovial fluid and in providing regulatory factors for cartilage and bone turnover. BACH2, transcription regulator protein BACH2; FLS, fibroblast-like synoviocytes; GM-CSF, granulocyte macrophage colony-stimulating factor; M-CSF, macrophage colony-stimulating factor; MQ, macrophages; NFATC1, nuclear factor of activated T cells, cytoplasmic 1;  PPARγ, peroxisome proliferator-activated receptor gamma; RANKL, receptor activator of nuclear factor kappa-B ligand; SPIC, transcription factor Spi-C.

Figure 3

What are the effector pathways, transcriptional regulators and activators of synovial tissue macrophages in healthy donors and in patients with RA in remission? The constitutive presence of tissue macrophages in healthy synovial tissue and the sustained presence of some synovial tissue macrophages in patients with RA during remission suggests that these subpopulations have a role in maintaining and reinstating synovial homeostasis. However, little is known about the effector pathways and stimuli and transcription factors that execute their function. Synovial tissue macrophages in healthy subjects express the scavenger receptor CD163, suggesting that they are strongly phagocytic. They also express MHC-II, IL-1R-antagonist and the inhibitor of bone degradation, osteoprotegerin (OPG), and they are negative for proinflammatory cytokines (eg, TNF and IL1β) and the bone resorption cytokine RANKL, suggesting a joint protective function against inflammation and damage. In contrast, the phenotype of proinflammatory synovial tissue macrophages is well described. These cells are MHC-II positive and produce a broad range of inflammatory mediators (eg, TNF, IL1β, IL-6, IL-23 and S100A8/9) that drive local and systemic pathologies in RA. Their activation is sustained by a variety of local stimuli that include endogenous TLR ligands, immune complexes, oxidised lipids, hypoxia and integrin-mediated contact with synovial fibroblasts and T cells. This proinflammatory programme is executed by NFκB, IRF5, STAT1/5 and HIF1α and is maintained by microRNA-155. FcγR, Fc gamma receptor; GM-CSFR, granulocyte macrophage colony-stimulating factor receptor; IL, interleukin; IRF, interferon regulatory factor; LXRα, liver X receptor alpha; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; RA, rheumatoid arthritis; STAT, signal transducer and activator of transcription; TLR, Toll-like receptors; TNF, tumour necrosis factor.

Figure 4

Putative contribution of tissue-specific (signal 1) and the local polarisation environment (signal 2) to the phenotype of synovial tissue macrophages in homeostasis and inflammation. Tissue-specific cues (signal 1), for example, from stretched synovial fibroblasts (FLS) to macrophage precursors may induce the synovial tissue macrophage programme that maintains synovial homeostasis. In the inflamed RA synovium, tissue-specific cues are modulated by proinflammatory on-demand signals (signal 2; eg, provided by epigenetically changed FLS, leucocytes and hypoxia). Most understanding is based on experimental models, and it is unknown whether distinct human synovial tissue macrophage subpopulations would respond differently to the synovial tissue-specific and ‘on-demand’ proinflammatory cues. Dissecting these pathways will improve our understanding of the mechanisms of successful versus failed joint homeostasis. MC, mast cells; MQ, macrophages; Neu, neutrophils; TF, transcription factor; Th17/Th1, T helper 1 and 17.