Rheumatoid arthritis results from a dysregulation in host immunity. Since our initial cloning of murine macrophage migration inhibitory factor (MIF), we have focused on the role of this mediator in the pathogenesis of rheumatoid arthritis. We showed that anti-MIF is protective in experimental arthritis and we reported on MIF's ability to override glucocorticoid immunosuppression, induce sustained activation of ERK1/2 MAP kinases, and promote inflammation by inhibiting activation-induced apoptosis. The importance of MIF in human disease was validated by our discovery of high-expression MIF alleles and their association with rheumatoid arthritis severity;these data were confirmed recently in a larger multi- center study and extended to juvenile idiopathic arthritis. In the currently funded period, we elucidated MIF function by creating genetic models for the complete and cell-lineage specific deletion of MIF (MIF-KO, mif flox), and we developed a """"""""knock-in"""""""" mouse encoding a mutant MIF that resolved questions about the protein's enigmatic tautomerase activity. We also established that MIF signal transduction requires a complex of two proteins: CD74, which binds MIF, and CD44, which initiates signaling by activating Src family tyrosine kinases. In this competitive renewal, we will focus on the function of the recently elucidated MIF receptor.
Our Specific Aims are: 1. Define the Role of the MIF Receptor Complex (CD74/CD44) in the Adaptive Immune Response. Our working hypothesis is that signaling through the MIF receptor sustains the survival of activated T lymphocytes and regulates the adaptive immune response. 2. Define the Functional Importance of the MIF Signaling Receptor, CD44, and of CD44 Variant Isoforms in the Immunopathology of Rheumatoid Arthritis. The expression of CD44 splice variants in T cells is associated with an enhanced trafficking response;and in stromal cells, with an increase in invasive phenotype. Our working hypothesis is that MIF induces the alternative splicing of CD44, which regulates MIF-dependent responses and contributes to the immunopathogenesis of rheumatoid arthritis. 3. Identify High-potency, Small Molecule Antagonists of the MIF Binding Receptor (CD74). Structure-function studies indicate that MIF's N-terminal region binds to the CD74 component of the MIF receptor. We will evaluate small molecules that were rationally designed to bind to the MIF N-terminal region for their ability to inhibit MIF interaction with CD74 and ameliorate experimentally-induced arthritis. The information to be gained will have broad application because it will provide mechanistic insight into how the MIF receptor complex (CD74/CD44) contributes to the immunopathology of rheumatoid arthritis. The translational impact of these studies is that a more precise definition of MIF-receptor action will accelerate the development of small molecule MIF inhibitors. Such inhibitors may show greatest efficacy in those patients with high-expression MIF alleles and who manifest an MIF-dependent form of inflammatory disease.

Public Health Relevance

The host immune response plays a critical role in the pathogenesis of rheumatoid arthritis. The immune cytokine, macrophage migration inhibitory factor (MIF), is encoded in a functionally polymorphic genetic locus and is associated with the severity of rheumatoid arthritis. The goal of this proposal is to show how the MIF cell surface receptor regulates the immune response and how different structural forms of the receptor promote immunopathology. We also will test a new class of rationally designed small molecules for their ability to block MIF interaction with its receptor. If successful, this information will lead to the accelerated development of MIF inhibitors for the treatment of rheumatoid arthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR050498-09
Application #
8310257
Study Section
Special Emphasis Panel (ZRG1-MOSS-H (02))
Program Officer
Mao, Su-Yau
Project Start
2004-01-23
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
9
Fiscal Year
2012
Total Cost
$471,874
Indirect Cost
$186,754
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
You, Sungyong; Koh, Jung Hee; Leng, Lin et al. (2018) The Tumor-Like Phenotype of Rheumatoid Synovium: Molecular Profiling and Prospects for Precision Medicine. Arthritis Rheumatol 70:637-652
Benedek, Gil; Meza-Romero, Roberto; Jordan, Kelley et al. (2017) MIF and D-DT are potential disease severity modifiers in male MS subjects. Proc Natl Acad Sci U S A 114:E8421-E8429
Yao, Jie; Leng, Lin; Sauler, Maor et al. (2016) Transcription factor ICBP90 regulates the MIF promoter and immune susceptibility locus. J Clin Invest 126:732-44
Yoo, Seung-Ah; Leng, Lin; Kim, Bum-Joon et al. (2016) MIF allele-dependent regulation of the MIF coreceptor CD44 and role in rheumatoid arthritis. Proc Natl Acad Sci U S A 113:E7917-E7926
de Souza, H S; Tortori, C A; Lintomen, L et al. (2015) Macrophage migration inhibitory factor promotes eosinophil accumulation and tissue remodeling in eosinophilic esophagitis. Mucosal Immunol 8:1154-65
Gu, Ran; Santos, Leilani L; Ngo, Devi et al. (2015) Macrophage migration inhibitory factor is essential for osteoclastogenic mechanisms in vitro and in vivo mouse model of arthritis. Cytokine 72:135-45
De la Cruz-Mosso, U; Bucala, R; Palafox-Sánchez, C A et al. (2014) Macrophage migration inhibitory factor: association of -794 CATT5-8 and -173 G>C polymorphisms with TNF-? in systemic lupus erythematosus. Hum Immunol 75:433-9
Binsky-Ehrenreich, I; Marom, A; Sobotta, M C et al. (2014) CD84 is a survival receptor for CLL cells. Oncogene 33:1006-16
Fan, Huapeng; Kao, Wenping; Yang, Yuan H et al. (2014) Macrophage migration inhibitory factor inhibits the antiinflammatory effects of glucocorticoids via glucocorticoid-induced leucine zipper. Arthritis Rheumatol 66:2059-70
Meza-Romero, Roberto; Benedek, Gil; Yu, Xiaolin et al. (2014) HLA-DR?1 constructs block CD74 expression and MIF effects in experimental autoimmune encephalomyelitis. J Immunol 192:4164-73

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