期刊
FRONTIERS IN IMMUNOLOGY
卷 10, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2019.02508
关键词
leukocyte-endothelial interaction; sepsis; bacterial infection; fungal infection; leukocyte transcriptomes; endothelial transcriptomes; interferon pathways
类别
资金
- Graduate School of Medical Science, University Medical Center Groningen
- Radboud University Medical Center Hypatia Tenure Track Grant
- European Society of Clinical Microbiology and Infectious Diseases (ESCMID)
- NWO Gravitation Netherlands Organ-on-Chip Initiative [024.003.001]
- Spinoza grant of the Netherlands Organization for Scientific Research
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 of leukocytes but not 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-alpha antibody in leukocyte-released mediators before exposing to endothelial cells, we identified specific roles for IL-1 and TNF-alpha 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-alpha 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 TNF alpha signaling, in mediating leukocyte-endothelial interaction in infections.
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