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

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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.

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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).

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Author notes

  1. Bárbara N. Porto

    Present address: Program in Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada

  2. Gabriela F. de Souza and Stéfanie P. Muraro contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Clinical and Experimental Immunology, Infant Center, School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil

    Gabriela F. de Souza, Stéfanie P. Muraro, Leonardo D. Santos, Amanda G. da Silva, Ana Paula D. de Souza & Bárbara N. Porto

  2. Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, RJ, Brazil

    Ana Paula T. Monteiro & Patrícia T. Bozza

  3. Laboratory of Pediatric Respirology, Infant Center, School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil

    Renato T. Stein

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  1. Gabriela F. de Souza
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  2. Stéfanie P. Muraro
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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.

Corresponding author

Correspondence to Bárbara N. Porto.

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de Souza, G.F., Muraro, S.P., Santos, L.D. et al. Macrophage migration inhibitory factor (MIF) controls cytokine release during respiratory syncytial virus infection in macrophages. Inflamm. Res. 68, 481–491 (2019). https://doi.org/10.1007/s00011-019-01233-z

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  • DOI: https://doi.org/10.1007/s00011-019-01233-z

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