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Macrophage migration inhibitory factor (MIF) controls cytokine release during respiratory syncytial virus infection in macrophages

  • Gabriela F. de Souza
  • Stéfanie P. Muraro
  • Leonardo D. Santos
  • Ana Paula T. Monteiro
  • Amanda G. da Silva
  • Ana Paula D. de Souza
  • Renato T. Stein
  • Patrícia T. Bozza
  • Bárbara N. PortoEmail author
Original Research Paper
  • 74 Downloads

Abstract

Objective and design

Respiratory syncytial virus (RSV) is the major cause of infection in children up to 2 years old and reinfection is very common among patients. Tissue damage in the lung caused by RSV leads to an immune response and infected cells activate multiple signaling pathways and massive production of inflammatory mediators like macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine. Therefore, we sought to investigate the role of MIF during RSV infection in macrophages.

Methods

We evaluated MIF expression in BALB/c mice-derived macrophages stimulated with different concentrations of RSV by Western blot and real-time PCR. Additionally, different inhibitors of signaling pathways and ROS were used to evaluate their importance for MIF expression. Furthermore, we used a specific MIF inhibitor, ISO-1, to evaluate the role of MIF in viral clearance and in RSV-induced TNF-α, MCP-1 and IL-10 release from macrophages.

Results

We showed that RSV induces MIF expression dependently of ROS, 5-LOX, COX and PI3K activation. Moreover, viral replication is necessary for RSV-triggered MIF expression. Differently, p38 MAPK in only partially needed for RSV-induced MIF expression. In addition, MIF is important for the release of TNF-α, MCP-1 and IL-10 triggered by RSV in macrophages.

Conclusions

In conclusion, we demonstrate that MIF is expressed during RSV infection and controls the release of pro-inflammatory cytokines from macrophages in an in vitro model.

Keywords

Respiratory syncytial virus MIF Macrophage migration inhibitory factor Macrophages Cytokines Signaling pathways 

Notes

Acknowledgements

This study was supported by CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico—Grant nr. 456282/2014-9 to Bárbara N. Porto and Grant nr. 481366/2011-3 to Renato T. Stein). Gabriela F. de Souza was recipient of a scholarship from CNPq and Stéfanie P. Muraro was recipient of a scholarship from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil).

Author contributions

BNP and GFS conceived and designed the study. GFS, SPM, APTM, LDS and AGS performed the experiments. BNP, GFS and SPM performed the statistical analysis and interpreted the data. BNP, GFS and SPM wrote the manuscript. BNP, APDS, RTS and PTB critically revised the draft. All authors contributed to the manuscript revision and approved the submitted version.

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Gabriela F. de Souza
    • 1
  • Stéfanie P. Muraro
    • 1
  • Leonardo D. Santos
    • 1
  • Ana Paula T. Monteiro
    • 2
  • Amanda G. da Silva
    • 1
  • Ana Paula D. de Souza
    • 1
  • Renato T. Stein
    • 3
  • Patrícia T. Bozza
    • 2
  • Bárbara N. Porto
    • 1
    • 4
    Email author
  1. 1.Laboratory of Clinical and Experimental Immunology, Infant Center, School of MedicinePontifical Catholic University of Rio Grande do Sul (PUCRS)Porto AlegreBrazil
  2. 2.Laboratory of ImmunopharmacologyOswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ)Rio de JaneiroBrazil
  3. 3.Laboratory of Pediatric Respirology, Infant Center, School of MedicinePontifical Catholic University of Rio Grande do Sul (PUCRS)Porto AlegreBrazil
  4. 4.Program in Translational MedicineThe Hospital for Sick ChildrenTorontoCanada

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