Over the last few years, we have gained a deeper understanding of the molecular processes of established inflammatory arthritis – when people go to their doctor with symptoms. Less is known about the initial steps of disease. If we knew more about what’s happening in arthritic joints at the onset of disease, we might be able to design better drugs and prevent disease progression.
A new study led by Dr Barbora Schonfeldova, within Professor Irina Udalova’s research group at the Kennedy Institute of Rheumatology, has helped to uncover the early steps of inflammatory arthritis. The researchers looked at how macrophages shape the environment in our joints early in disease.
Specifically, the researchers looked at the synovium, which is a tissue layer that lines our joints and produces a lubricating fluid to keep them moving. In arthritis, a patient’s own immune cells attack the synovium and cause inflammation and pain. This results in synovial fluid which is too thick or too thin, but either way is less able to move our joints smoothly.
Macrophages are a major type of immune cell throughout the body which are also present in the synovium. They usually surround and kill pathogens like bacteria, helping to protect us against infection. In arthritis, however, some macrophage subsets drive an attack on the synovium. This leads to chronic pain and inflammation of the joint.
Recent studies have revealed that there are many subsets of macrophage in the synovium, each of which with the potential to play different roles in inflammation. However, with a notable exception of VSIG4-positive macrophages in the synovium lining, the roles and specific locations of these macrophages are largely unknown. In this study, the researchers looked at a subset of macrophages known as ‘resistin-like molecule alpha (RELMα)-positive’. RELMα is a protein involved in multiple inflammatory diseases.
Dr Schonfeldova and colleagues found that within the synovium, these RELMα-positive macrophages are mostly found in the perivascular niche close to blood vessels. These macrophages were found to produce CCL2, a cytokine which attracts monocytes, another type of immune cell, at the onset of arthritis. Within the inflamed synovium, the monocytes recruited by CCL2 may then differentiate into macrophages, which then drive further inflammation in the joint.
This study suggests that these RELMα-positive macrophages within the perivascular niche could therefore be a promising drug target in arthritis – switching off their ability to recruit monocytes may lead to less inflammation.
Dr Barbora Schonfeldova said: ‘This project began as an MSc Immunology project for Marah Chibwana, which I designed and co-supervised. I am so thrilled it has developed into a more comprehensive study and was published at the end of my DPhil. I am also pleased about influencing Marah’s career, who subsequently joined the lab as a Rhodes Scholar and is the second author on this paper.’
Dr Irina Udalova said: ‘This is an exciting new development in defining functions of heterogeneous populations of synovial macrophages and their interactions with other structural and immune cells. More revelations about unexpected functions of other yet unmapped populations of macrophages to come – watch this space!’
The KIR is grateful to the Wellcome Trust, Versus Arthritis, and the Kennedy Trust for Rheumatology Research, who provided funds which enabled this research.