C3a– C3aR1 –Mediated Interactions Between Fibroblast–Like Synoviocytes and Macrophages Promote the Progression of Rheumatoid Arthritis

Objective The inflammatory microenvironment in rheumatoid arthritis (RA) synovium is highly complex, comprising functional units known as cellular neighborhoods (CNs). However, how cell interactions within CNs shape the inflammatory microenvironment in RA remains unclear. Methods Here, we used imaging mass cytometry and single‐cell RNA sequencing to dissect the CNs within RA synovium, uncovering critical cell‐cell interactions and evaluating whether disrupting interaction signals could alleviate disease severity in a collagen‐induced arthritis (CIA) mouse model. Results Our findings revealed that CNs enriched with fibroblast‐like synoviocytes (FLSs) and immune cells, particularly FLSs and macrophages, were more frequent in RA synovium compared with osteoarthritis. Further single‐cell RNA sequencing analysis showed that FLSs specifically up‐regulated complement C3 whereas macrophages displayed high levels of the C3 receptor, C3aR1. Interestingly, C3a derived from the FLS‐enhanced type I interferon response in macrophages, and the blockade of the C3a‐C3aR1 signaling reduced the secretion of interferon β in macrophages, thereby affecting FLS activation. Additionally, inhibition of C3a‐C3aR1 signaling attenuated the severity of CIA mice with decreased immune cell infiltration, reduced FLS activation, and lessened bone destruction. Conclusion Our study suggests that FLS promotes synovial inflammation via interaction with macrophages through a C3a‐C3aR1 signaling‐mediated positive feedback regulation. Thus, targeting C3a‐C3aR1 signaling might provide a new therapeutic strategy for RA.