Leukocyte transcriptional signatures dependent on LPS dosage in human endotoxemia

• Published in: Journal of leukocyte biology Vol. 106; no. 5; pp. 1153 - 1160
• Main Authors: Khan, Hina N., Perlee, Desiree, Schoenmaker, Lieke, der Meer, Anne‐Jan, Franitza, Marek, Toliat, Mohammad Reza, Nürnberg, Peter, Zwinderman, Aeilko H., der Poll, Tom, Scicluna, Brendon P.
• Format: Journal Article
• Language: English
• Published: United States John Wiley and Sons Inc 01.11.2019
• Subjects: Adult; blood; Dose-Response Relationship, Immunologic; Endotoxemia - chemically induced; Endotoxemia - immunology; Endotoxemia - pathology; Gene Expression Profiling; Gene Expression Regulation - drug effects; Gene Expression Regulation - immunology; genomics; Host Defense & Pathophysiology; Humans; immune response; Leukocytes - immunology; Leukocytes - pathology; Lipopolysaccharides - toxicity; Male; Oligonucleotide Array Sequence Analysis; Transcription, Genetic - drug effects; Transcription, Genetic - immunology; immune response; genomics; blood
• ISSN: 0741-5400; 1938-3673; 1938-3673
• DOI: 10.1002/JLB.4A0219-050R

The host immune response is characterized by a complex interplay of signal‐specific cellular transcriptional responses. The magnitude of the immune response is dependent on the strength of the external stimulus. Knowledge on leukocyte transcriptional responses altered in response to different stimulus dosages in man is lacking. Here, we sought to identify leukocyte transcriptional signatures dependent on LPS dose in humans. Healthy human volunteers were administered 1 ng/kg (n = 7), 2 ng/kg (n = 6), or 4 ng/kg (n = 7) LPS intravenously. Blood was collected before (pre‐LPS) and 4 h after LPS administration. Total RNA was analyzed by microarrays and generalized linear models. Pathway analysis was performed by using Ingenuity pathway analysis. Leukocyte transcriptomes altered per LPS dosage were predominantly shared, with 47% common signatures relative to pre‐LPS. A univariate linear model identified a set of 3736 genes that exhibited a dependency on differing LPS dosages. Neutrophil, monocyte, and lymphocyte counts explained 38.9% of the variance in the LPS dose‐dependent gene set. A multivariate linear model including leukocyte composition delineated a set of 295 genes with a dependency on LPS dose. Evaluation of the 295 gene signature in patients with sepsis due to abdominal infections showed significant correlations. Promoter regions of the LPS dose gene set were enriched for YY1, EGR1, ELK1, GABPA, KLF4, and REL transcription factor binding sites. Intravenous injection of 1, 2, or 4 ng/kg LPS was accompanied by both shared and distinct leukocyte transcriptional alterations. These data may assist in assessing the severity of the insult in patients with abdominal sepsis. Shared and distinct leukocyte transcriptional signatures in response to different LPS dosages in human endotoxemia.