title: Macrophage migration inhibitory factor receptor CD74 mediates alphavirus-induced arthritis and myositis in murine models of alphavirus infection.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Griffith University, Gold Coast Campus, Southport, Queensland, Australia.
authors.forename: Lara J
authors.initials: LJ
authors.lastname: Herrero
authors.forename: Kuo-Ching
authors.initials: KC
authors.lastname: Sheng
authors.forename: Peng
authors.initials: P
authors.lastname: Jian
authors.forename: Adam
authors.initials: A
authors.lastname: Taylor
authors.forename: Zhisheng
authors.initials: Z
authors.lastname: Her
authors.forename: Belinda L
authors.initials: BL
authors.lastname: Herring
authors.forename: Angela
authors.initials: A
authors.lastname: Chow
authors.forename: Yee-Sin
authors.initials: YS
authors.lastname: Leo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hickey
authors.forename: Eric F
authors.initials: EF
authors.lastname: Morand
authors.forename: Lisa F P
authors.initials: LF
authors.lastname: Ng
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Suresh
authors.initials: S
authors.lastname: Mahalingam
mesh_terms: D018354:Alphavirus Infections / Q000150:complications* / Q000473:pathology; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology; D001170:Arthritis, Infectious / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D002646:Chikungunya virus / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology; D009220:Myositis / Q000473:pathology / Q000503:physiopathology* / Q000821:virology*; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012398:Ross River virus / Q000502:physiology; D012720:Severity of Illness Index
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D018925:Chemokines; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D011971:Receptors, Immunologic; C045084:invariant chain; C033184:macrophage migration inhibitory factor receptor
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