Macrophage migration inhibitory factor receptor CD74 mediates alphavirus-induced arthritis and myositis in murine models of alphavirus infection

Lara J Herrero, Kuo-Ching Sheng, Peng Jian, Adam Taylor, Zhisheng Her, Belinda Herring, Angela Chow, Yee-Sin Leo, Michael John Hickey, Eric Francis Morand, Lisa F P Ng, Richard Bucala, Suresh Mahalingam

Research output: Contribution to journalArticleResearchpeer-review

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. 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.
Original languageEnglish
Pages (from-to)2724 - 2736
Number of pages13
JournalArthritis and Rheumatism
Volume65
Issue number10
DOIs
Publication statusPublished - 2013

Cite this

Herrero, Lara J ; Sheng, Kuo-Ching ; Jian, Peng ; Taylor, Adam ; Her, Zhisheng ; Herring, Belinda ; Chow, Angela ; Leo, Yee-Sin ; Hickey, Michael John ; Morand, Eric Francis ; Ng, Lisa F P ; Bucala, Richard ; Mahalingam, Suresh. / Macrophage migration inhibitory factor receptor CD74 mediates alphavirus-induced arthritis and myositis in murine models of alphavirus infection. In: Arthritis and Rheumatism. 2013 ; Vol. 65, No. 10. pp. 2724 - 2736.
@article{1250bea7aa754686bc10e493e8e40362,
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. 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.",
author = "Herrero, {Lara J} and Kuo-Ching Sheng and Peng Jian and Adam Taylor and Zhisheng Her and Belinda Herring and Angela Chow and Yee-Sin Leo and Hickey, {Michael John} and Morand, {Eric Francis} and Ng, {Lisa F P} and Richard Bucala and Suresh Mahalingam",
year = "2013",
doi = "10.1002/art.38090",
language = "English",
volume = "65",
pages = "2724 -- 2736",
journal = "Arthritis and Rheumatology",
issn = "2326-5191",
publisher = "Wiley-Blackwell",
number = "10",

}

Herrero, LJ, Sheng, K-C, Jian, P, Taylor, A, Her, Z, Herring, B, Chow, A, Leo, Y-S, Hickey, MJ, Morand, EF, Ng, LFP, Bucala, R & Mahalingam, S 2013, 'Macrophage migration inhibitory factor receptor CD74 mediates alphavirus-induced arthritis and myositis in murine models of alphavirus infection' Arthritis and Rheumatism, vol. 65, no. 10, pp. 2724 - 2736. https://doi.org/10.1002/art.38090

Macrophage migration inhibitory factor receptor CD74 mediates alphavirus-induced arthritis and myositis in murine models of alphavirus infection. / Herrero, Lara J; Sheng, Kuo-Ching; Jian, Peng; Taylor, Adam; Her, Zhisheng; Herring, Belinda; Chow, Angela; Leo, Yee-Sin; Hickey, Michael John; Morand, Eric Francis; Ng, Lisa F P; Bucala, Richard; Mahalingam, Suresh.

In: Arthritis and Rheumatism, Vol. 65, No. 10, 2013, p. 2724 - 2736.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Macrophage migration inhibitory factor receptor CD74 mediates alphavirus-induced arthritis and myositis in murine models of alphavirus infection

AU - Herrero, Lara J

AU - Sheng, Kuo-Ching

AU - Jian, Peng

AU - Taylor, Adam

AU - Her, Zhisheng

AU - Herring, Belinda

AU - Chow, Angela

AU - Leo, Yee-Sin

AU - Hickey, Michael John

AU - Morand, Eric Francis

AU - Ng, Lisa F P

AU - Bucala, Richard

AU - Mahalingam, Suresh

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

UR - http://www.ncbi.nlm.nih.gov/pubmed/23896945

U2 - 10.1002/art.38090

DO - 10.1002/art.38090

M3 - Article

VL - 65

SP - 2724

EP - 2736

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

SN - 2326-5191

IS - 10

ER -