A Systems Biology Approach to the Analysis of Subset-Specific Responses to Lipopolysaccharide in Dendritic Cells

Abstract

Dendritic cells (DCs) are critical for regulating CD4 and CD8 T cell immunity, controlling Th1, Th2, and Th17 commitment, generating inducible Tregs, and mediating tolerance. It is believed that distinct DC subsets have evolved to control these different immune outcomes. However, how DC subsets mount different responses to inflammatory and/or tolerogenic signals in order to accomplish their divergent functions remains unclear. Lipopolysaccharide (LPS) provides an excellent model for investigating responses in closely related splenic DC subsets, as all subsets express the LPS receptor TLR4 and respond to LPS in vitro. However, previous studies of the LPS-induced DC transcriptome have been performed only on mixed DC populations. Moreover, comparisons of the in vivo response of two closely related DC subsets to LPS stimulation have not been reported in the literature to date. We compared the transcriptomes of murine splenic CD8 and CD11b DC subsets after in vivo LPS stimulation, using RNA-Seq and systems biology approaches. We identified subset-specific gene signatures, which included multiple functional immune mediators unique to each subset. To explain the observed subset-specific differences, we used a network analysis approach. While both DC subsets used a conserved set of transcription factors and major signalling pathways, the subsets showed differential regulation of sets of genes that ‘fine-tune’ the network Hubs expressed in common. We propose a model in which signalling through common pathway components is ‘fine-tuned’ by transcriptional control of subset-specific modulators, thus allowing for distinct functional outcomes in closely related DC subsets. We extend this analysis to comparable datasets from the literature and confirm that our model can account for cell subset-specific responses to LPS stimulation in multiple subpopulations in mouse and man.

Identifying Dendritic Cell–Related Genes Through a Co-Expression Network to Construct a 12-Gene Risk-Scoring Model for Predicting Hepatocellular Carcinoma Prognosis

“…Patients with high DC expression show worse prognosis than patients with low DC expression in HCC. DCs are regarded as crucial regulators of T-cell responses and involved in pathology via activating T cells and B cells ( Hancock and et al, 2014 ; van Uden et al, 2019 ). Plasmacytoid dendritic cells (pDCs) have been documented in multiple primary and metastatic human cancers ( Vermi et al, 2011 ).…”

Genome-wide association analysis reveals variants on chromosome 19 that contribute to childhood risk of chronic otitis media with effusion

“…differences in respiratory tract pathogen load and in exposure to antigens causing hypersensitivity reactions may elicit different pathogenic pathways. In this context it is intriguing that in a systems biology study of LPS stimulation of dendritic cell subpopulations, two of the genes within the region on chromosome 19 of interest, namely PLD3 and SERTAD1, have been found to be selectively regulated in CD11b and CD8 dendritic cell subpopulations, respectively, which are distinct dendritic cell populations that regulate Th2 and Th1 immune responses, respectively 31 . Thus, one might argue that the apparent contradiction of opposite risk alleles might be due to differences in pathogenic pathways caused by different environmental factors in Finnish vs. British children although the ultimate result is similar in terms of prolonged middle ear effusion characteristic of COME.…”

“…None of our genes are included in gene categories that are enriched in previously suggested genes associated with OM, implying that a gene in this region may contribute to OM pathogenesis through a novel mechanism. Nevertheless, it is quite plausible that a gene, like PLD3 or SERTAD1 or both, that is highly up-regulated upon stimulation by pathogens and that is specifically regulated in dendritic cell subsets that control distinct immune response types 31 would be a relevant candidate gene for OM.…”

Suppression of Dendritic Cell-Derived IL-12 by Endogenous Glucocorticoids Is Protective in LPS-Induced Sepsis

“…Genome-wide microarray analyses have identified several apoptotic regulators, including Bim and GILZ, in the regulation of GC-induced apoptosis [reviewed in 47 ]. A recent study comparing subset-specific transcriptomes of murine splenic CD8 + and CD11b + DC subsets found that at steady state, CD8 + DCs had 3- to 26-fold higher levels of transcripts encoding the proapoptotic genes Bad , Bim , and BCL2l14 ( BclG ) [ 48 ]. Moreover, 24 hr after LPS challenge mRNA encoding the anti-apoptotic Bcl-xL was 20-fold lower in CD8 + compared to CD11b + DCs.…”