title: MIF allele-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.
authors.affiliation: College of Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul 06591, Korea.
authors.forename: Seung-Ah
authors.initials: SA
authors.lastname: Yoo
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Bum-Joon
authors.initials: BJ
authors.lastname: Kim
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Pathricia V
authors.initials: PV
authors.lastname: Tilstam
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Kim
authors.affiliation: College of Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul 06591, Korea.
authors.forename: Jin-Sun
authors.initials: JS
authors.lastname: Kong
authors.affiliation: College of Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul 06591, Korea.
authors.forename: Hyung-Ju
authors.initials: HJ
authors.lastname: Yoon
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Aihua
authors.initials: A
authors.lastname: Liu
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Tian
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Yan
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Maor
authors.initials: M
authors.lastname: Sauler
authors.affiliation: Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, 80539 Munich, Germany.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Bernhagen
authors.affiliation: Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Ritchlin
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Patty
authors.initials: P
authors.lastname: Lee
authors.affiliation: College of Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul 06591, Korea.
authors.forename: Chul-Soo
authors.initials: CS
authors.lastname: Cho
authors.affiliation: College of Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul 06591, Korea; richard.bucala@yale.edu wan725@catholic.ac.kr.
authors.forename: Wan-Uk
authors.initials: WU
authors.lastname: Kim
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06510; richard.bucala@yale.edu wan725@catholic.ac.kr.
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D019556:COS Cells; D002448:Cell Adhesion; D002465:Cell Movement; D002522:Chlorocebus aethiops; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism*
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D008263:Macrophage Migration-Inhibitory Factors; D011453:Prostaglandins
keywords: CD44; CD74; MIF; autoimmunity; immunogenetics