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Critical role for macrophage migration inhibitory factor (MIF) in Ross River virus-induced arthritis and myositis
Lara J Herrero1, Michelle Nelson, Anon Srikiatkhachorn
1Virus and Inflammation Research Group, Faculty of Applied Science, University of Canberra, Canberra, ACT 2601, Australia.
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.
Insights
Macrophage migration inhibitory factor (MIF) drives severe alphavirus-induced arthritis. Blocking MIF in mice reduced disease severity, suggesting MIF as a therapeutic target for viral polyarthritis.
Area of Science:
- Virology
- Immunology
- Rheumatology
Background:
- Arthrogenic alphaviruses cause widespread polyarthritis outbreaks globally.
- The precise mechanisms of alphavirus-induced polyarthritis are not fully understood, but macrophages are implicated.
- Macrophage migration inhibitory factor (MIF) is a key cytokine in rheumatoid arthritis pathogenesis.
Purpose of the Study:
- To investigate the role of MIF in alphavirus-induced arthritis.
- To characterize the impact of MIF on disease severity and pathology in a mouse model of Ross River virus (RRV) infection.
Main Methods:
- Utilized a mouse model of RRV-induced arthritis, comparing wild-type (WT) and MIF-deficient (MIF(-/-)) mice.
- Assessed disease severity, inflammation, tissue damage, and viral titers.
- Investigated the effects of MIF reconstitution and MIF antagonist treatment.
Main Results:
- WT mice infected with RRV developed severe arthritis with elevated MIF expression, inflammation, and tissue damage.
- MIF(-/-) mice exhibited milder disease, reduced inflammation, and less muscle destruction despite similar viral loads.
- MIF reconstitution exacerbated RRV disease, while MIF antagonism ameliorated it in WT mice.
Conclusions:
- MIF plays a crucial role in determining the clinical severity of alphavirus-induced musculoskeletal disease.
- Targeting MIF presents a potential therapeutic strategy for managing debilitating arthritis associated with alphaviral infections.
- Early intervention with MIF-blocking pharmaceuticals could mitigate arthritis severity in alphavirus infections.