New rheumatoid arthritis research published in the Journal of Experimental Medicine suggests that synovial lining macrophages are important initiators of inflammation in the tissue between joints, challenging the idea that these cells mainly act at the resolution of inflammation. Understanding the elusive early steps of rheumatoid arthritis could lead to better treatments for patients.
Rheumatoid arthritis (RA) is a chronic inflammatory condition which occurs when the immune system attacks the lining of the joints. This lining, called the synovium, usually produces a liquid which helps healthy joints to move smoothly. In RA, the attacking immune cells cause the synovium to instead become inflamed, stiff and painful. In humans, the disease manifests years after the first inflammatory pathways were activated, making it very hard to understand these initial driving steps. Understanding the first steps of RA could inform early treatment options and lead to better long-term outcomes for patients.
Funded by the Wellcome Trust Investigator Award to Irina Udalova, Professor of Molecular Immunology, the Kennedy scientists used state-of-the-art microscopy of mouse tissues to study immune cell dynamics in a RA joint. They found that early in RA initiation, macrophages in the synovial lining become activated and produce chemokines – chemical messengers of the immune system required for coordination of an immune response. This macrophage activation and chemokine production causes neutrophils to be recruited where they drive inflammation in the joint.
Lead author Dr Kristina Zec, now Versus Arthritis Foundation Fellow, said: “We are so proud and excited about our new study that changes the way we look at macrophages in the synovium. We discover that synovial lining macrophages, which have previously been shown to resolve joint inflammation, can also act as initiators of the recruitment of neutrophils at the onset of inflammation”.
Within the synovium, neutrophils drive the misplaced immune attack, which often leads to chronic inflammation and pain. The researchers have also identified a protein called IRF5 that was required for synovial lining macrophage activation. When it was specifically deleted in the lining macrophages, neutrophil recruitment was significantly impaired.
“These results shift the current dogma in the field and open new avenues for targeted therapeutic interventions aimed at pacifying overly active macrophages early in the disease”, said Irina Udalova, the senior author on the study.