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

Abstract

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.immunogenetics | autoimmunity | MIF | CD44 | CD74

Protease activated‐receptor 4 activation as a model of persistent bladder pain: Essential role of macrophage migration inhibitory factor and high mobility group box 1

“…daily; Calbiochem, Burlington, MA, USA), or a MIF receptor CD74 coupling inhibitor, MIF098 (40 mg/kg, with 40% HP‐P‐CD and 10% PEG400 in H 2 O i.p. b.i.d …”

MIF family cytokines in cardiovascular diseases and prospects for precision-based therapeutics

“…CD74 is sufficient for MIF/MIF-2 high affinity cell surface binding, but CD44 is essential for downstream MAP kinase (e.g. ERK1/2, JNK), Akt kinase and AMPK signaling [33, 39, 40]. MIF engagement of CD74 leads to the horizontal membrane recruitment of CD44; both proteins then undergo intracellular phosphorylation to initiate downstream signal transduction [39, 41].…”

“…ERK1/2, JNK), Akt kinase and AMPK signaling [33, 39, 40]. MIF engagement of CD74 leads to the horizontal membrane recruitment of CD44; both proteins then undergo intracellular phosphorylation to initiate downstream signal transduction [39, 41]. MIF additionally activates the chemokine receptors CXCR2 and CXCR4, alone or in a complex with CD74 [42].…”

Endothelial cell‐secreted MIF reduces pericyte contractility and enhances neutrophil extravasation

“…Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine known to exert significant proinflammatory effects (8)(9)(10)(11). MIF is expressed by many cell types, including EC.…”