Fractalkine/CX3CL1, the unique member of the CX3C chemokine subfamily, is involved in the pathogenesis cancer, atherosclerosis, glomerulonephritis, rheumatoid arthritis, HIV disease and sepsis. In contrast with other chemokines, Fractalkine/CX3CL1 exists in two forms, each mediating distinct biological actions. The membrane-anchored protein, which is expressed primarily on the endothelium, serves as an adhesion protein promoting the retention of monocytes and T cells. The soluble form originates from extracellular proteolysis by proteases, such as tumour necrosis factor-a converting enzyme (also known as ADAM17) and ADAM10. The secreted form resembles more a conventional chemokine and strongly induces chemotaxis and causes migration of natural killer cells, cytotoxic T lymphocytesand macrophages.
Rheumatoid Arthritis is a chronic symmetric polyarticular joint autoimmune disease that primarily affects the small joints of the hands and feet. Inflammation is characterized by infiltration of inflammatory cells such as macrophages, B cells, T cells, and dendritic cells into the joint, leading to the proliferation of synoviocytes and the destruction of cartilage and bone. Migration of leukocytes into the synovium is regulated through a multistep process, involving interactions between leukocytes and endothelial cells, cellular adhesion molecules, and chemokines and their receptors. Rheumatoid Arthritis
pathogenesis is characterized by the recruitment and the retention of monocytes and T lymphocytes into joints. Produced in
response to inflammatory stimuli such as 1L-1β, TNF-α, IFN-γ, and lipopolysaccharide (LPS), chemokines further stimulate synovial fibroblasts and chondrocytes to release inflammatory mediators and matrix metalloproteinases, leading to cartilage degradation and pannus (i.e., newly vascularized tissue found between the bone and synovium) formation. Angiogenesis and cell proliferation are enhanced by chemokines, leading to synovial hyperplasia. Synovial fibroblasts, chondrocytes, and leukocytes release chemokines that can induce autocrine and paracrine stimulation of synovial cells, resulting in tissue destruction in Rheumatoid Arthritis joints.
Fractalkine/CX3CL1 plays a dual role in Rheumatoid Arthritis: 1) acting as a chemotactic agent for monocytes and lymphocytes, and 2) as a cellular adhesion molecule. A high percentage of macrophages within Rheumatoid Arthritis synovium express the CX3CR1 receptor, suggesting fractalkine/CX3CL1 participates in the development of Rheumatoid Arthritis. Ruth et al. reported high levels of soluble fractalkine/CX3CL1 in Rheumatoid Arthritis synovial fluid. In peripheral blood and synovial fluid, mainly monocytes express fractalkine/ CX3CL1, while macrophages, fibroblasts, endothelial, and dendritic cells expressed this chemokine in synovial tissue. This study also found that a significant portion (~80%) of monocytes have CX3CR1, whereby fractalkine/CX3CL1 may recruit them to the synovium to become the primary driving force of inflammation. These levels of fractalkine/CX3CL1 in Rheumatoid Arthritis synovial fluid were significantly elevated compared to that in SF from osteoarthritis (OA) patients. Further studies have evaluated the levels of fractalkine/CX3CL1 expressing leukocytes in Rheumatoid Arthritis. Nanki et al. found that a substantial portion (53.4% vs. 19.2%) of Rheumatoid Arthritis CD8+ T cells bear surface CX3CR1 when compared to the cells derived from a healthy population. Administration of fractalkine/ CX3CL1-specific monoclonal antibody to mice significantly reduced the clinical measure of arthritis and inflammatory infiltrate on histological sections. There was also a marked reduction in the incidence of arthritis and a reduction in the trafficking of monocytes to the synovium. Volin et al. demonstrated that SF depleted of fractalkine/CX3CL1 has lower angiogenic effect compared to control SF.
Clinical studies have shown that TNF-α inhibitors decrease fractalkine/CX3CL1 expression in Rheumatoid Arthritis . Several trials have provided evidence that infliximab is safe and effective in treating Rheumatoid Arthritis, although some patients (20–40%) have little to no clinical response to TNF-α therapy. Odai et al. observed that infliximab treatment in Rheumatoid Arthritis inhibits the downstream signaling cascade, effectively decreasing production of inflammatory cytokines, including fractalkine/CX3CL1, in Rheumatoid Arthritis.
Jones BA, et al. Fractalkine/CX3CL1: A Potential New Target for Inflammatory Diseases. Molecular Interventions. 2010;10(5):263-270.