Macrophage migration inhibitory factor–CD74 receptor complex (MIF–CD74)

The Macrophage migration inhibitory factor (MIF)–CD74 receptor complex is a critical signaling axis in the pathogenesis of rheumatoid arthritis (RA), particularly within fibroblast-like synoviocytes (FLS). MIF is a pleiotropic pro-inflammatory cytokine (UniProt P14174) that binds to its high-affinity cell-surface receptor, CD74 (the invariant chain of the MHC class II complex, UniProt P04233), often requiring the recruitment of CD44 to initiate intracellular signaling (Leng et al., 2003, PMID: 12707293). In the context of RA, FLS exhibit an activated, tumor-like phenotype characterized by excessive proliferation, reduced apoptosis, and the secretion of degradative enzymes like matrix metalloproteinases (MMPs). Activation of the MIF–CD74 pathway in these cells triggers the MAPK/ERK and PI3K/Akt pathways, which sustain this aggressive cellular behavior and promote joint destruction (Morand et al., 2006, PMID: 16547551). Therapeutic strategies targeting this pathway include monoclonal antibodies against MIF (e.g., Imalumab) or CD74 (e.g., Milatuzumab), as well as small-molecule inhibitors of MIF's tautomerase activity like ISO-1. By disrupting this interaction, researchers aim to reduce synovial inflammation and prevent the structural damage characteristic of chronic inflammatory arthritis.

Other names

MIF/CD74 complexHLA-DR-associated invariant chainGlycosylation-inhibiting factorMIF-CD74-CD44 signaling axis

Antagonism of the MIF-CD74 interaction or inhibition of MIF tautomerase activity to prevent downstream pro-inflammatory signaling.