Abstract
BackgroundLipopolysaccharide (endotoxin, LPS) is a strong inducer of the innate immune response. It is widespread in our environment, e.g. in house dust and contributes to asthma. Compared to humans, horses are even more sensitive to LPS. However, data on LPS effects on the equine transcriptome are very limited. Using RNA-seq we analysed LPS-induced differences in the gene expression in equine peripheral blood mononuclear cells at the gene and gene-network level in two half-sib families and one group of unrelated horses.Results24 h-LPS challenge of equine immune cells resulted in substantial changes in the transcriptomic profile (1,265 differentially expressed genes) showing partial overlap with human data. One of the half-sib families showed a specific response different from the other two groups of horses. We also identified co-expressed gene modules that clearly differentiated 24 h-LPS- from non-stimulated samples. These modules consisted of 934 highly interconnected genes and included genes involved in the immune response (e.g. IL6, CCL22, CXCL6, CXCL2), however, none of the top ten hub genes of the modules have been annotated as responsive to LPS in gene ontology.ConclusionsUsing weighted gene co-expression network analysis we identified ten co-expressed gene modules significantly regulated by in vitro stimulation with LPS. Apart from 47 genes (5%) all other genes highly interconnected within the most up- and down-regulated modules were also significantly differentially expressed (FDR < 0.05). The LPS-regulated module hub genes have not yet been described as having a role in the immune response to LPS (e.g. VAT1 and TTC25).
Highlights
Lipopolysaccharide is a strong inducer of the innate immune response
The 82 samples were derived from three different cohorts of healthy Warmblood horses: one group of horses that were unrelated at the parent level and two half-sibling families
We removed three outliers based on the sample dendrogram (Fig. 1) plus one additional sample that matched the same horse as an outlier removed in order to keep only the samples with both mock and LPS stimulations required for the differential expression analysis
Summary
Lipopolysaccharide (endotoxin, LPS) is a strong inducer of the innate immune response. When LPS enters the blood stream, most commonly through an intestinal lesion, it is opsonized by serum LPS-binding protein [4], which is recognized by Toll-like receptor 4 (TLR4) with the help of its co-receptor CD14 and another cell surface molecule, MD-2 [5, 6]. This recognition leads to a signalling cascade through MyD88and TRIF-dependent pathways [7], activating the NF-κB transcription factor and inducing expression and release of numerous cytokines, including TNF-α, IL-1, IL-6, and IL-10 [8, 9]. Sepsis is defined as a disrupted regulation of inflammation in the face of bacterial or other microbial infection, which can lead to tissue damage, organ
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