Researchers at Trinity College Dublin and St. Vincent’s University Hospital have identified a specific macrophage subtype in the joints of rheumatoid arthritis (RA) patients that could lead to earlier diagnosis and more targeted treatments. The study, published in Science Advances, details the cellular and genetic characteristics of joint inflammation in RA, offering insights into potential therapeutic targets and predictive biomarkers.
Identification of a Dominant Macrophage Subtype
The research team, led by Ursula Fearon, PhD, and Megan Hanlon, PhD, conducted RNA sequencing and metabolic analysis of macrophages in the synovium of RA patients, individuals at risk of RA, and healthy controls. They discovered a dominant macrophage subtype (CD40-expressing CD206+CD163+) in the inflamed RA synovium. This subtype was associated with disease activity and treatment response and was present even before clinical symptoms appeared.
Clinical Significance and Potential for Early Intervention
The identification of this early pathogenic macrophage cell/gene signature in the RA joint inflammatory environment presents a unique opportunity for early diagnosis and therapeutic intervention. According to Fearon, this breakthrough enhances the understanding of the initial stages of RA and its impact on patient progression and relapse. "Reprogramming of macrophages towards resolution of inflammation has the potential to be therapeutically targeted," she noted.
Macrophages and RA Pathogenesis
Rheumatoid arthritis, affecting approximately one percent of the population, is characterized by synovial inflammation, hyperplasia, and structural damage to cartilage and bone. It also leads to comorbidities such as atherosclerosis, diabetes, and cardiovascular disease. A significant proportion of patients do not respond to current treatments, making it impossible to predict who will develop severe disease and who will respond to treatment. This often results in a trial-and-error approach, potentially causing irreversible joint damage.
The study highlighted that while synovial tissue macrophages are the most common immune cells in the normal synovium, their function is not well understood. These macrophages are pivotal in joint destruction, with recent research uncovering diverse phenotypes in health and disease. The team's analysis identified the CD40-expressing CD206+CD163+ macrophage subtype as dominant in patients with active RA. These cells, which normally play a protective role, become pro-inflammatory in disease, releasing cytokines that induce inflammation and activating invasive fibroblasts that lead to cartilage and bone destruction.
Implications for Future Therapies
The researchers found that the CD40-expressing CD206+CD163+ macrophages were transcriptionally distinct, with unique tissue-resident gene signatures and metabolic capacities. Importantly, this macrophage subtype is present and activated in individuals at risk of developing RA, even before clinical signs and symptoms appear. The pro-inflammatory status of these macrophages is maintained by specific signaling and metabolic pathways within the joint, suggesting that targeting CD40 signaling could be a new strategy for patients who do not respond to current treatments.
Hanlon, now based at Harvard University, emphasized the possibility of using these macrophages as an early cellular biomarker of disease onset, leading to early treatment intervention. The study also revealed that protective barrier macrophages (CX3CR1+) were depleted in established RA, indicating a shift from protective to pro-inflammatory macrophages.
The authors concluded that uncovering the early molecular patterns that transform immunoregulatory macrophages into a dysfunctional inflammatory state may provide opportunities to reinstate joint homeostasis in patients with RA.
