Galectin-9 inhibition of the MIF-CD74/CD44 pathway suppresses chronic arthritis

The destructive potential of rheumatoid arthritis (RA) lies in the aggressive behavior of fibroblast-like synoviocytes (FLSs), which actively contribute to the erosion of cartilage and bone and may persist even in the face of apparent clinical remission. Therapeutic approaches targeting RA-FLSs have been developed to treat RA; however, there are no clinically approved drugs available at present. Here, single-cell RNA sequencing of RA-FLSs identified a distinct macrophage migration inhibitory factor (MIF)^high subset with mitochondrial and endoplasmic reticulum dysfunction. MIF^high conditions led to increased survival, proliferation, and migration of FLSs, along with the upregulation of CD44 and the CD44v6 isoform expression. We next explored whether a stable, recombinant form of galectin-9 (sGal-9), which acts as a CD44 blockade, regulates the MIF-induced aggressive phenotype of RA-FLSs. We found that sGal-9 remarkably reduced the increased proliferation, migration, and invasion of RA-FLSs by inhibiting the MIF-CD44 pathway. Moreover, both local and systemic administration of sGal-9 substantially inhibited excessive cartilage and bone destruction by RA-FLSs in a xenotransplantation arthritis model and alleviated the severity of collagen-induced arthritis in mice, comparable to Enbrel and tofacitinib. Conclusively, these data suggest that sGal-9 is effective at repressing destructive phenotypes of RA-FLSs as a novel anti-MIF agent.