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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02508

Leukocyte-released mediators in response to both bacterial and fungal infections trigger IFN pathways, independent of IL-1 and TNF-α, in endothelial cells

  • 1University Medical Center Groningen, Netherlands
  • 2Department of Genetics, University Medical Centre Groningen, Netherlands
  • 3Radboud University Nijmegen, Netherlands
  • 4Department of Internal Medicine, Radboud University Medical Center, Netherlands

In sepsis, dysregulated immune responses to infections cause damage to the host. Previous studies have attempted to capture pathogen-induced leukocyte responses. However, the impact of mediators released after pathogen-leukocyte interaction on endothelial cells, and how endothelial cell responses vary depending on the pathogen-type is lacking. Here, we comprehensively characterized the transcriptomic responses of human leukocytes and endothelial cells to Gram negative-bacteria, Gram positive-bacteria and fungi. We showed that whole pathogen lysates induced strong activation in leukocytes but not in endothelial cells. Interestingly, the common response of leukocytes to various pathogens converges on endothelial activation. By exposing endothelial cells to leukocyte-released mediators, we observed a strong activation of endothelial cells at both transcription and protein levels. By adding IL-1RA and TNF-α antibody in leukocyte-released mediators before exposing to endothelial cells, we identified specific roles for IL-1 and TNF-α in driving the most, but not all, endothelial activation. We also showed for the first time, activation of interferon response by endothelial cells in response to leukocyte-released mediators, independently from IL-1 and TNF-α pathways. Our study therefore, not only provides pathogen-dependent transcriptional changes in leukocytes and endothelial cells during infections, but also reveals a role for IFN, together with IL1 and TNFα signaling, in mediating leukocyte-endothelial interaction in infections.

Keywords: leukocyte-endothelial interaction, Sepsis, Bacterial infection, Fungal Infection, leukocyte transcriptomes, endothelial transcriptomes, Interferon pathways

Received: 04 Aug 2019; Accepted: 07 Oct 2019.

Copyright: © 2019 Le, Chu, Jaeger, Plantinga, Matzaraki, Withoff, Joosten, Netea, Wijmenga, Li, Moser and Kumar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Ms. Kieu T. Le, University Medical Center Groningen, Groningen, Netherlands, thienkieu64@gmail.com