Another Inflammatory Mediator Identified: Possible New Therapeutic Target?
What problem was studied?
One of the earliest events in rheumatoid arthritis is that leukocytes (white blood cells) travel into inflamed synovial tissue. Synovial tissue forms the joint lining and produces lubricating and cushioning synovial fluid. A number of chemicals in the body facilitate this process of leukocyte recruitment; these growth factors are called chemokines, or inflammatory mediators. A new chemokine, CXCL16, has been identified and researchers are studying it to determine its role in the inflammatory process of rheumatoid arthritis (RA). Therapies designed to block the activity or inhibit the production of chemokines are important tools in the treatment of inflammatory arthritides.
What was done in the study?
Using a variety of in vivo (in live subjects) and in vitro (in test tubes) techniques, researchers – including current Arthritis Foundation-funded researchers Drs. Jeffrey H. Ruth and Christy C. Park and previous grant awardees Drs. Shiva Shahrara and Alisa E. Koch – measured the participation of CXCL16 and its cellular receptor, CXCR6, in leukocyte migration to the synovial tissue in RA. Synovial fluid samples were obtained from patients with RA, osteoarthritis, and other inflammatory rheumatic diseases. Peripheral blood samples were taken from patients with different forms of arthritis and from healthy volunteers. Synovial tissue samples were obtained from RA patients undergoing total joint replacement, and normal synovial tissue samples were obtained from fresh autopsies or amputations.
The researchers used the various human blood and tissue samples to run a series of laboratory tests, some using mice that had synovial tissue specimens from people with RA grafted onto their backs. The researchers were able to inject fluorescent dye-tagged human cells into these chimeric mice to evaluate the migration of the cells to the graft. They were then able to reveal the effects of CXCL16 on that migration.
What were the study results?
The researchers found that the cytokine in question, CXCL16, was active in the synovial tissue and synovial fluid of people with RA, but was not active to the same extent in the people with OA or controls. The researchers found that CXCL16 is a strong biologic mediator that attracts leukocytes to the synovial tissue in people with RA. They were also able to halt the signaling cascade and the migratory patterns of leukocytes to the inflamed synovial tissue by blocking the intracellular pathways used by CXCL16.
What’s the relevance to people with arthritis?
The researchers found that CXCL16 functions to aggressively recruit leukocytes to inflammatory synovial tissue. This knowledge can lead to the development of new medications that block the action of CXCL16 and hence alter the inflammatory process in RA.
Researchers are currently examining the activity of CXCL16 in new blood vessel formation, a process called angiogenesis. If CXCL16 is indeed angiogenic, its potential as a therapeutic target in RA would be strengthened. This is because researchers would be able to not only block cellular migration to RA synovial tissue, but would also be able to inhibit the blood vessels these destructive cells use to reach the synovium.
Source: Arthritis & Rheumatism, Volume 54, No. 3