title: Critical role for macrophage migration inhibitory factor (MIF) in Ross River virus-induced arthritis and myositis.
abstract: 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.
authors: Virus and Inflammation Research Group, Faculty of Applied Science, University of Canberra, Canberra, ACT 2601, Australia.
authors: Lara J
authors: LJ
authors: Herrero
authors: Michelle
authors: M
authors: Nelson
authors: Anon
authors: A
authors: Srikiatkhachorn
authors: Ran
authors: R
authors: Gu
authors: Surapee
authors: S
authors: Anantapreecha
authors: Günter
authors: G
authors: Fingerle-Rowson
authors: Richard
authors: R
authors: Bucala
authors: Eric
authors: E
authors: Morand
authors: Leilani L
authors: LL
authors: Santos
authors: Suresh
authors: S
authors: Mahalingam
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001168:Arthritis / Q000378:metabolism / Q000503:physiopathology / Q000821:virology*; D018932:Chemokine CCL2 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000502:physiology*; D006652:Histological Techniques; D007371:Interferon-gamma / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009220:Myositis / Q000378:metabolism / Q000503:physiopathology / Q000821:virology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012398:Ross River virus / Q000378:metabolism*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D008263:Macrophage Migration-Inhibitory Factors; D007371:Interferon-gamma; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse