Seung-Ah Yooa,1, Lin Lengb,1, Bum-Joon Kimb,2, Xin Dub, Pathricia V. Tilstamb, Kyung Hee Kimb, Jin-Sun Konga, Hyung-Ju Yoona, Aihua Liub, Tian Wangb, Yan Songb, Maor Saulerb, Jurgen Bernhagenc, Christopher T. Ritchlind, Patty Leeb, Chul-Soo Choa, Wan-Uk Kima,3, and Richard Bucalab,3
aCollege of Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul 06591, Korea;
bDepartment of Medicine, Yale University School of Medicine, New Haven, CT 06510;
cVascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universitat Munchen, Ludwig-Maximilians-Universitat Munchen, 80539 Munich, Germany;
dDepartment of Medicine, University of Rochester Medical Center, Rochester, NY 14642
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
1S.-A.Y. and L.L. contributed equally to this work.
2Present address: Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 03080, Korea.
3To whom correspondence may be addressed.
Author contributions: L.L., W.-U.K., and R.B. designed research; S.-A.Y., L.L., B.-J.K., X.D., P.V.T., K.H.K., J.-S.K., H.-J.Y., A.L., T.W., Y.S., M.S., and C.-S.C. performed research; J.B. and C.T.R. contributed new reagents/analytic tools; L.L., B.-J.K., K.H.K., M.S., J.B., P.L., W.-U.K., and R.B. analyzed data; and W.-U.K. and R.B. wrote the paper.