Fractalkine, exciting new target for RA treatment

“From the clinician's point of view, the most important points to remember about [FKN] in RA are that it and its interaction with CX3CR1 may be an important mediator of both leucocyte infiltration and activation, and neoangiogenesis in the rheumatoid joint,” Dr. Murphy told MSKreport.com. She also pointed out that treatments aimed at FKN might help reduce a second problem associated with RA.

“Given the evidence implicating [FKN] in the pathogenesis of atherosclerosis and RA, there is a plausible explanation linking synovial-based events with premature vascular disease in RA, suggesting a potential therapeutic target with dual benefit.”

Structure explains why FKN acts as both chemokine and adhesion molecule

FKN has a 76-amino acid extracellular domain attached to a mucin-like stalk hooked to a transmembrane domain and a 37-amino acid intracellular tail. The stalk holds the extracellular domain above the cell surface, which allows presentation to leukocytes and cell adhesion. The extracellular domain also can be cleaved by proteolysis to yield soluble FKN, which is chemotactic for both monocytes and T-cells. FKN binds to the CX3CR1 receptor.

“FKN is a powerful chemoattractant agent, mediating adhesion, facilitating transmigration, and thus the synovial influx of pro-inflammatory cells. It possesses significant angiogenic capability and can lead to upregulation of MMPs [matrix metalloproteinases] that are implicated in cartilage degradation. Thus, FKN may play an important role in the initiation and/or propagation of the inflammatory insult in RA,” Dr. Murphy said.

She explained that FKN is upregulated on both endothelium and fibroblast like synoviocytes within synovial tissue, leading to leucocyte adhesion/inflammatory cell infiltration and T-cell activation, respectively. FKN also increases cytokine secretion, including IL-1 and IL-6 from peripheral monocytes. “Importantly, both monocytes and T-cells (the key components of the inflammatory infiltrate in RA) express CX3CR1, leading to their recruitment to, and transmigration across, synovial blood vessels.”

Safer target than other chemokines in RA?

Many chemokine-receptor ligand interactions demonstrate redundancy in their pairing, but the FKN-CX3CR1 interaction is specific. According to Dr. Murphy, this eliminates the risk that might be associated with targeting a less selective pairing (with multiple receptor and downstream effectors brought into play). “This selectivity also facilitates research into the specific functions of CX3CR1 activation.”

To date there has been one study of FKN inhibition in a mouse colagen-induced arthritis model, which showed that administration of an anti-FKN monoclonal antibody reduced arthritis incidence, joint signs, clinical scores, and histological severity scores in animals that developed arthritis, according to Dr. Murphy. She would like to see studies to determine whether inhibition of FKN or its receptor might protect against synovial neovascularization.

“[FKN] has received attention in the vascular biology field for some time and studies, particularly in atherosclerosis, would indicate that its inhibition may well be beneficial in athero-reduction, as indicated by transgenic mouse models lacking CX3CR1. In this context, [FKN] plays a role in directing leucocyte influx to the vessel wall, as well as contributing to the accumulation of neointimal smooth muscle cells. It is possible that the upregulation of [FKN], and its role in inflammation in [RA], may also enhance the inflammatory process at the vessel-wall interface elsewhere, leading to premature ischemic heart disease.”

Moreover, in RA, CX3CR1 is expressed on a novel subset of senescent CD4 cells that lack the costimulatory molecule CD28. Dr. Murphy said that the lymphocyte population has been linked to premature atherosclerosis in RA. This might be the link between synovial and vascular inflammation in RA.

“Taken together, these findings would suggest that [FKN] is involved in the inflammatory process at both a synovial and systemic level, with a resultant increase in premature vascular disease, which may be reduced by its inhibition,” Dr. Murphy concluded.

Useful RA biomarker?

Synovial fluid levels of FKN are generally higher in RA than in osteoarthritis or other inflammatory arthritides. Dr. Murphy noted that this might also make FKN useful in differential diagnosis of undifferentiated inflammatory arthritides.

Reference

1. Murphy G, Caplice N, Molloy M. Fractalkine in rheumatoid arthritis: a review to date. Rheumatology. 2008;47:1446-1451.

Fractalkine, exciting new target for RA treatment | Arthritis Information