Targeting pathogenic fibroblast-like synoviocyte subsets in rheumatoid arthritis

Abstract

Fibroblast-like synoviocytes (FLSs) play a central role in RA pathogenesis and are the main cellular component in the inflamed synovium of patients with rheumatoid arthritis (RA). FLSs are emerging as promising new therapeutic targets in RA. However, fibroblasts perform many essential functions that are required for sustaining tissue homeostasis. Direct targeting of general fibroblast markers on FLSs is challenging because fibroblasts in other tissues might be altered and side effects such as reduced wound healing or fibrosis can occur. To date, no FLS-specific targeted therapies have been applied in the clinical management of RA. With the help of high-throughput technologies such as scRNA-seq in recent years, several specific pathogenic FLS subsets in RA have been identified. Understanding the characteristics of these pathogenic FLS clusters and the mechanisms that drive their differentiation can provide new insights into the development of novel FLS-targeting strategies for RA. Here, we discuss the pathogenic FLS subsets in RA that have been elucidated in recent years and potential strategies for targeting pathogenic FLSs.

Keywords: Fibroblast-like synoviocytes; Immune homeostasis; Inflammation; Rheumatoid arthritis; Therapeutic target.

Fig. 1

Pathogenic FLS subsets in RA. FLSs in the inflamed synovium can be anatomically distinguished into lining FLSs and sublining FLSs. FAPα, PDPN, and CDH-11 are expressed mainly on lining FLSs and also on sublining FLSs. The expression of FAPα, PDPN, and CDH-11 may resemble the pathogenic FLS phenotype, as targeting these markers can ameliorate arthritis in animal models of RA. Pathogenic FLSs in RA can be further subclassified into immune-interacting FLSs and bone-effector FLSs based on the expression of CD90 and CD55/PRG4, respectively. CD90 is expressed on sublining FLSs and can be used to designate proinflammatory FLS subsets that mediate inflammation persistence. Among CD90⁺ FLSs, a subset with high HLA-DRA expression that can secrete several proinflammatory cytokines and chemokines is substantially expanded in RA patients

Fig. 2

CDH-11, FAPα, PDPN, CD90 and CD248 are relatively specific synovial FLS markers. Targeting pathogenic FLS surface markers with specific antibodies, inhibitors, vaccines or CART cell might be potential strategies for the treatment of RA

Fig. 3

Targeting signaling pathways that drive pathogenic FLS differentiation might be a potential strategy for the treatment of RA. FLSs exhibit high phenotypic plasticity, and different cytokines or cells can stimulate the differentiation of different FLS subsets. Targeting NOTCH3 signaling at FLSs might affect CD90 expression in FLSs. IFN-γ-mediated stimulation of JAK-STAT1 signaling might also block HLA-DR expression in CD90⁺FLSs, which has proinflammatory effects during RA pathogenesis

Fig. 4

Restoring FLS homeostasis might be a potential strategy for the treatment of RA. FLS subsets in active RA patients are different from those in healthy individuals or patients in remission. Transforming proinflammatory and aggressive FLSs in RA patients into resolving or tissue repair FLSs via normal fibroblasts or mesenchymal stem cells might restore FLS homeostasis and alleviate RA