Macrophage migration inhibitory factor receptor CD74 mediates alphavirus-induced arthritis and myositis in murine models of alphavirus infection
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Updated: May 9, 2026
An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
Published on: June 6, 2025
Lara J Herrero1, Kuo-Ching Sheng, Peng Jian
1Griffith University, Gold Coast Campus, Southport, Queensland, Australia.
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.
Insights
CD74 deficiency significantly reduced symptoms and tissue damage in mouse models of Ross River virus and chikungunya virus infections. This suggests CD74 and MIF are key targets for treating alphaviral arthritis.
Area of Science:
- Virology
- Immunology
- Pathogenesis
Background:
- Arthrogenic alphaviruses like Ross River virus (RRV) and chikungunya virus (CHIKV) cause widespread, debilitating arthritis.
- Macrophage migration inhibitory factor (MIF) is a critical inflammatory factor in alphaviral disease pathogenesis.
Purpose of the Study:
- To investigate the role of CD74, a cell surface receptor for MIF, in RRV- and CHIKV-induced alphavirus arthritis.
- To characterize CD74's function in the immune response to alphaviral infections.
Main Methods:
- Utilized mouse models of RRV and CHIKV infection.
- Assessed CD74's role through histologic analysis, real-time PCR, flow cytometry, and plaque assays.
Main Results:
- CD74 knockout mice exhibited milder clinical symptoms and reduced tissue damage compared to wild-type mice.
- Leukocyte infiltration, particularly monocytes and NK cells, was decreased in CD74 knockout mice.
- CD74 deficiency led to increased monocyte apoptosis but did not affect migratory capacity.
Conclusions:
- CD74 regulates immune responses to alphaviral infection by influencing cellular recruitment and survival.
- MIF and CD74 are critical mediators of alphaviral disease.
- Targeting MIF and CD74 may offer therapeutic potential for alphaviral arthritides.
