Blocking one receptor on cells could halt rheumatoid arthritis

Dr Shiva Shahrara’s team has made the discovery

Scientists have discovered that the activation of a receptor provokes the inflammation and bone degradation of rheumatoid arthritis, they reported in the Journal of Immunology. The findings point to a new therapeutic target to interrupt the cycle of inflammation and bone erosion in rheumatoid arthritis.
Rheumatoid arthritis is a progressive autoimmune inflammatory disease of the joints. Swelling and pain, caused by certain cells flooding into the joints, is a hallmark of the disease, along with progressive bone loss. The new research has found that the process begins with the triggering of a single receptor on a group of white blood cells.
Toll-like receptor 5 (TLR5) is found on myeloid, or marrow-derived, cells that migrate from the blood into affected joints. The experts found that the receptor is much more abundant on myeloid cells in the fluid of joints in people with rheumatoid arthritis than in healthy people.
The same team previously discovered that activation of TLR5 causes abnormal blood vessel formation in the joints of people with rheumatoid arthritis. In the new study they found that the receptor also up-regulates a potent inflammatory molecule called TNF-alpha, which recruits even more myeloid cells into the joint, where they are transformed into bone-degrading cells called osteoclasts.
When the researchers placed TLR5-expressing myeloid cells next to joint fluid from people with rheumatoid arthritis, the cells migrated into the fluid. But if the receptor was blocked by an antibody, cell migration towards the fluid was significantly reduced.
The researchers also found that levels of TNF-alpha increased in joint fluid from people with rheumatoid arthritis when myeloid cells with activated TLR5 were present. People with rheumatoid arthritis who take anti-TNF-alpha drugs have lower levels of TLR5 on their myeloid cells, suggesting that a positive feedback loop exists between TLR5 and TNF-alpha, so that an elevation in one causes an increase in the other.
“TLR5 does it all,” says Dr Shiva Shahrara, who is involved in the work. “Not only do TLR5 and TNF-alpha regulate each other, but they work synergistically to attract more myeloid cells into the joint, where they are transformed into bone-eroding cells.”
Based on lab studies in mice, Dr Shahrara thinks a drug that prevents TLR5 activation could slow or prevent the inflammation and bone erosion of later-stage rheumatoid arthritis in patients.
“When TLR5 is activated, it initiates a vicious feedback loop that results in a worsening of both the inflammatory and erosive features of rheumatoid arthritis,” Dr Shahrara. “The receptor is a major driver of inflammation and bone degradation. Blocking this receptor could have significant therapeutic value in interrupting joint swelling and bone loss in patients with rheumatoid arthritis.”

To read the original research click here.