C3a‐C3aR1‐mediated interactions between fibroblast‐like synoviocytes and macrophages promote the progression of rheumatoid arthritis

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. Here, we utilized imaging mass cytometry (IMC) 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 collagen‐induced arthritis (CIA) mouse model. Our findings revealed that CNs enriched with fibroblast‐like synoviocytes (FLS) and immune cells, particularly FLS and macrophages, were more frequent in RA synovium compared to osteoarthritis (OA). Further single‐cell RNA sequencing analysis showed that FLS specifically upregulated complement C3 while macrophages displayed high level of C3 receptor, C3aR1. Interestingly, C3a derived from FLS enhanced type I interferon response in macrophages, and blockade of the C3a‐C3aR1 signaling reduced secretion of IFN‐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 less bone destruction. 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.