Inflammatory Cell Migration in Rheumatoid Arthritis: A Comprehensive Review

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that primarily affects the joints. Self-reactive B and T lymphocytes cooperate to promote antibody responses against self proteins and are major drivers of disease. T lymphocytes also promote RA independently of B lymphocytes mainly through the production of key inflammatory cytokines, such as IL-17, that promote pathology. While the innate signals that initiate self-reactive adaptive immune responses are poorly understood, the disease is predominantly caused by inflammatory cellular infiltration and accumulation in articular tissues, and by bone erosions driven by bone-resorbing osteoclasts. Osteoclasts are giant multinucleated cells formed by the fusion of multiple myeloid cells that require short-range signals, such as the cytokines MCSF and RANKL, for undergoing differentiation. The recruitment and positioning of osteoclast precursors to sites of osteoclast differentiation by chemoattractants is an important point of control for osteoclastogenesis and bone resorption. Recently, the GPCR EBI2 and its oxysterol ligand 7a, 25 dihydroxycholesterol, were identified as important regulators of osteoclast precursor positioning in proximity to bone surfaces and of osteoclast differentiation under homeostasis. In chronic inflammatory diseases like RA, osteoclast differentiation is also driven by inflammatory cytokines such as TNFa and IL-1, and can occur independently of RANKL. Finally, there is growing evidence that the chemotactic signals guiding osteoclast precursors to inflamed articular sites contribute to disease and are of great interest. Furthering our understanding of the complex osteoimmune cell interactions should provide new avenues of therapeutic intervention for RA.

Keywords: Cell migration; Osteoclast precursors; Osteoclasts; Rheumatoid arthritis.

Fig. 1

Trafficking of osteoclast precursors in the bone marrow (BM), blood, and peripheral tissues. Monocytic osteoclast precursor cells (OCP) and inflammatory monocytes (Inf Mono) migrate into osteoclastogenic niches where osteoblasts (OB) and osteocytes provide important signals for osteoclast differentiation (MCSF and RANKL). EBI2 directs the migration of OCP to the endosteum, where the EBI2 ligand 7α, 25-OHC is presumably abundant. CX₃CR1 promotes the retention of OCP in BM parenchyma, and possibly directs cells to the endosteum in response to CX₃CL1 produced by OB. OB also express CCR1 ligands (e.g. CCL9) and CCR1 may also direct OCP to sites of osteoclast differentiation. S1PR1 is essential for the egress of monocytic cells in the bone marrow as they follow S1P gradients into the circulation and inflammatory monocytes egress via CCR2. CXCR4 is likely to guide OCP away from sites of osteoclastogenesis given that its ligand CXCL12 is abundant parenchymal and perivacular mesenchymal stromal cells, while it is reduced in OBs. The CB2 ligand 2-AG is likely abundant in the BM sinusoids, and may guide OCP away from osteoclastogenic niches. Both circulatory OCP and inflammatory monocytes re-enter into BM by unknown mechanisms.

Fig. 2

Osteoclasts are located in close proximity to blood vessels in the bone marrow. Image acquired using two-photon microscopy of calvaria bone marrow of TRAP^Red reporter mouse. Osteoclasts (white); blood vessels (dashed line) were visualized with injection of dextran-FITC; and bone (gray). Scale bar= 30μm

Fig. 3

Trafficking of monocytic osteoclast precursors (OCP) into inflamed joints. Cells with osteoclastogenic potential include CD11b^−/loLy6C^hi, CD11b⁺GR-1⁻, and DCs. In RA, sinusoidal fibroblastic cells provide RANKL, which can be induced by IL-17 provided by Th17 cells. The cytokines TNF-α, IL-1, and IL-6, which may be locally secreted by macrophages also promote osteoclast differentiation under inflammatory conditions. S1P receptor expression on OCPs possibly directs cells into the synovial tissue where S1P is upregulated during inflammation. CXCR4 also likely directs cells into the synovial tissue with fibroblasts, and possibly other cells, express high levels of CXCL12. Selective antagonism of CB2 inhibits the migration of monocytes into the synovium, indicating that 2-Ag levels may be present in synovial fluid. CXCR2, CX₃CR1, CCR1, CCR2, and CCR5 are also implicated in inflammatory cell recruitment into the inflamed articular space.