Critical role for macrophage migration inhibitory factor (MIF) in Ross River virus-induced arthritis and myositis

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-07, Vol.108 (29), p.12048-12053
• Main Authors: Herrero, Lara J, Nelson, Michelle, Srikiatkhachorn, Anon, Gu, Ran, Anantapreecha, Surapee, Fingerle-Rowson, Günter, Bucala, Richard, Morand, Eric, Santos, Leilani L, Mahalingam, Suresh
• Format: Article
• Language: English
• Subjects: Analysis of Variance; animal models; Animals; Ankle joint; antagonists; Arthritis; Arthritis - metabolism; Arthritis - physiopathology; Arthritis - virology; Biological Sciences; blood serum; Chemokine CCL2 - metabolism; Cytokines; Disease models; drugs; Enzyme-Linked Immunosorbent Assay; Epidemiology; Gene Expression Regulation - physiology; Histological Techniques; humans; Infections; Inflammation; Interferon-gamma - metabolism; Intramolecular Oxidoreductases - antagonists & inhibitors; Intramolecular Oxidoreductases - metabolism; Joint diseases; macrophage migration inhibitory factors; Macrophage Migration-Inhibitory Factors - antagonists & inhibitors; Macrophage Migration-Inhibitory Factors - metabolism; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; muscles; myositis; Myositis - metabolism; Myositis - physiopathology; Myositis - virology; Pathogenesis; Reverse Transcriptase Polymerase Chain Reaction; Rheumatoid arthritis; rivers; Rodents; Ross River virus; Ross River virus - metabolism; therapeutics; tissues; Viral diseases; viral load; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1101089108

Arthrogenic alphaviruses, such as Ross River virus (RRV), chikungunya, Sindbis, mayaro and o'nyong-nyong viruses circulate endemically worldwide, frequently causing outbreaks of polyarthritis. The exact mechanisms of how alphaviruses induce polyarthritis remain ill defined, although macrophages are known to play a key role. Macrophage migration inhibitory factor (MIF) is an important cytokine involved in rheumatoid arthritis pathogenesis. Here, we characterize the role of MIF in alphavirus-induced arthritides using a mouse model of RRV-induced arthritis, which has many characteristics of RRV disease in humans. RRV-infected WT mice developed severe disease associated with up-regulated MIF expression in serum and tissues, which corresponded to severe inflammation and tissue damage. MIF-deficient (MIF⁻/⁻) mice developed mild disease accompanied by a reduction in inflammatory infiltrates and muscle destruction in the tissues, despite having viral titers similar to WT mice. In addition, reconstitution of MIF into MIF⁻/⁻ mice exacerbated RRV disease and treatment of mice with MIF antagonist ameliorated disease in WT mice. Collectively, these findings suggest that MIF plays a critical role in determining the clinical severity of alphavirus-induced musculoskeletal disease and may provide a target for the development of antiviral pharmaceuticals. The prospect being that early treatment with MIF-blocking pharmaceuticals may curtail the debilitating arthritis associated with alphaviral infections.