Document Detail

Macrophage migration inhibitory factor receptor CD74 mediates alphavirus-induced arthritis and myositis in murine models of alphavirus infection.
MedLine Citation:
PMID:  23896945     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: Arthrogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) circulate worldwide. This virus class causes debilitating illnesses that are characterized by arthritis, arthralgia, and myalgia. In previous studies, we identified macrophage migration inhibitory factor (MIF) as a critical inflammatory factor in the pathogenesis of alphaviral diseases. The present study was undertaken to characterize the role of CD74, a cell surface receptor of MIF, in both RRV- and CHIKV-induced alphavirus arthritides.
METHODS: Mouse models of RRV and CHIKV infection were used to investigate the immunopathogenesis of arthritic alphavirus infection. The role of CD74 was assessed using histologic analysis, real-time polymerase chain reaction, flow cytometry, and plaque assay.
RESULTS: In comparison to wild-type mice, CD74-/- mice developed only mild clinical features and had low levels of tissue damage. Leukocyte infiltration, characterized predominantly by inflammatory monocytes and natural killer cells, was substantially reduced in the infected tissue of CD74-/- mice, but production of proinflammatory cytokines and chemokines was not decreased. CD74 deficiency was associated with increased monocyte apoptosis, but had no effect on monocyte migratory capacity. Consistent with these findings, alphaviral infection resulted in a dose-dependent up-regulation of CD74 expression in human peripheral blood mononuclear cells, and serum MIF levels were significantly elevated in patients with RRV or CHIKV infection.
CONCLUSION: CD74 appears to regulate immune responses to alphaviral infection through its effects on cellular recruitment and survival. These findings suggest that both MIF and CD74 play a critical role in mediating alphaviral disease, and blocking these factors with novel therapeutic agents could substantially ameliorate the pathologic manifestations.
Lara J Herrero; Kuo-Ching Sheng; Peng Jian; Adam Taylor; Zhisheng Her; Belinda L Herring; Angela Chow; Yee-Sin Leo; Michael J Hickey; Eric F Morand; Lisa F P Ng; Richard Bucala; Suresh Mahalingam
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Arthritis and rheumatism     Volume:  65     ISSN:  1529-0131     ISO Abbreviation:  Arthritis Rheum.     Publication Date:  2013 Oct 
Date Detail:
Created Date:  2013-10-04     Completed Date:  2014-02-10     Revised Date:  2014-10-09    
Medline Journal Info:
Nlm Unique ID:  0370605     Medline TA:  Arthritis Rheum     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2724-36     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2013 by the American College of Rheumatology.
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MeSH Terms
Alphavirus Infections / complications*,  pathology
Antigens, Differentiation, B-Lymphocyte / genetics,  physiology*
Apoptosis / physiology
Arthritis, Infectious / etiology*,  pathology,  physiopathology*
Cells, Cultured
Chemokines / metabolism
Chikungunya virus / physiology
Cytokines / metabolism
Disease Models, Animal
Histocompatibility Antigens Class II / genetics,  physiology*
Mice, Inbred C57BL
Mice, Knockout
Monocytes / pathology
Myositis / pathology,  physiopathology*,  virology*
Receptors, Immunologic / deficiency,  genetics,  physiology*
Ross River virus / physiology
Severity of Illness Index
Grant Support
N01-HHSN272201100019C//PHS HHS; R01 AI042310/AI/NIAID NIH HHS; R01 AR049610/AR/NIAMS NIH HHS; R01 AR050498/AR/NIAMS NIH HHS; R01-AI-042310/AI/NIAID NIH HHS; R01-AR-050498/AR/NIAMS NIH HHS
Reg. No./Substance:
0/Antigens, Differentiation, B-Lymphocyte; 0/Chemokines; 0/Cytokines; 0/Histocompatibility Antigens Class II; 0/Receptors, Immunologic; 0/invariant chain; 0/macrophage migration inhibitory factor receptor

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