Abstract
Activation of dendritic cells by different pathogens induces the secretion of proinflammatory mediators resulting in local inflammation. Importantly, innate immunity must be properly controlled, as its continuous activation leads to the development of chronic inflammatory diseases such as psoriasis. Lipopolysaccharide (LPS) or peptidoglycan (PGN) induced tolerance, a phenomenon of transient unresponsiveness of cells to repeated or prolonged stimulation, proved valuable model for the study of chronic inflammation. Thus, the aim of this study was the identification of the transcriptional diversity of primary human immature dendritic cells (iDCs) upon PGN induced tolerance. Using SAGE-Seq approach, a tag-based transcriptome sequencing method, we investigated gene expression changes of primary human iDCs upon stimulation or restimulation with Staphylococcus aureus derived PGN, a widely used TLR2 ligand. Based on the expression pattern of the altered genes, we identified non-tolerizeable and tolerizeable genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (Kegg) analysis showed marked enrichment of immune-, cell cycle- and apoptosis related genes. In parallel to the marked induction of proinflammatory mediators, negative feedback regulators of innate immunity, such as TNFAIP3, TNFAIP8, Tyro3 and Mer are markedly downregulated in tolerant cells. We also demonstrate, that the expression pattern of TNFAIP3 and TNFAIP8 is altered in both lesional, and non-lesional skin of psoriatic patients. Finally, we show that pretreatment of immature dendritic cells with anti-TNF-α inhibits the expression of IL-6 and CCL1 in tolerant iDCs and partially releases the suppression of TNFAIP8. Our findings suggest that after PGN stimulation/restimulation the host cell utilizes different mechanisms in order to maintain critical balance between inflammation and tolerance. Importantly, the transcriptome sequencing of stimulated/restimulated iDCs identified numerous genes with altered expression to date not associated with role in chronic inflammation, underlying the relevance of our in vitro model for further characterization of IFN-primed iDCs.
Highlights
Plants and animals are constitutively exposed to various pathogens present in the environment including commensal and pathogenic microorganisms
We show that pretreatment of immature dendritic cells with anti-TNF-α inhibits the expression of IL-6 and CCL1 in tolerant iDCs and partially derepresses TNFAIP8 expression
In order to get a global view on the gene expression pattern of induced or tolerant primary human iDCs (Figure 1A), SAGE-Seq experiments were performed
Summary
Plants and animals are constitutively exposed to various pathogens present in the environment including commensal and pathogenic microorganisms. Septic shock, autoimmunity, atherosclerosis) [2] Numerous regulatory mechanisms, such as the production of anti-inflammatory cytokines or the induction of negative feedback regulators of the TLRs, i.e. members of the SOCS family [3,4] or TNFAIP3 [5] have been described that are preventing the host from the harmful side effects of uncontrolled inflammation. These molecules have pivotal role in the long-lasting hyporesponsiveness of the cells and organisms to prolonged/ repeated LPS stimulation, a phenomenon called LPS tolerance [6,7]. These data present a novel mechanism for the regulation of LPS tolerance, yet, little is known about transcriptional diversity of PGN tolerance
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