MIF allele-dependent regulation of the MIF coreceptor CD44 and role in rheumatoid arthritis

Significance High-expression alleles of the cytokine macrophage migration inhibitory factor (MIF) are associated with severe joint destruction in autoimmune arthritis, but the mechanism for this effect is unknown. High-genotypic MIF-expressing joint fibroblasts produce high levels of MIF under inflammatory stimulation to up-regulate the surface expression of the MIF signaling coreceptor CD44 and promote its alternative splicing into invasive, tumor-associated isoforms, which contribute to the invasive and tissue-destructive character of the rheumatoid joint synovium. These findings support a precision medicine approach to the treatment of rheumatoid arthritis by pharmacologically targeting the MIF pathway in high-genotypic MIF-expressing patients. Fibroblast-like synoviocytes mediate joint destruction in rheumatoid arthritis and exhibit sustained proinflammatory and invasive properties. CD44 is a polymorphic transmembrane protein with defined roles in matrix interaction and tumor invasion that is also a signaling coreceptor for macrophage migration inhibitory factor (MIF), which engages cell surface CD74. High-expression MIF alleles (rs5844572) are associated with rheumatoid joint erosion, but whether MIF signaling through the CD74/CD44 receptor complex promotes upstream autoimmune responses or contributes directly to synovial joint destruction is unknown. We report here the functional regulation of CD44 by an autocrine pathway in synovial fibroblasts that is driven by high-expression MIF alleles to up-regulate an inflammatory and invasive phenotype. MIF increases CD44 expression, promotes its recruitment into a functional signal transduction complex, and stimulates alternative exon splicing, leading to expression of the CD44v3–v6 isoforms associated with oncogenic invasion. CD44 recruitment into the MIF receptor complex, downstream MAPK and RhoA signaling, and invasive phenotype require MIF and CD74 and are reduced by MIF pathway antagonists. These data support a functional role for high-MIF expression alleles and the two-component CD74/CD44 MIF receptor in rheumatoid arthritis and suggest that pharmacologic inhibition of this pathway may offer a specific means to interfere with progressive joint destruction.