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E-GEOD-42573 - In vivo LPS responses in murine splenic CD8 and CD11b DC subsets

Status
Released on 1 July 2014, last updated on 31 July 2014
Organism
Mus musculus
Samples (4)
Protocols (3)
Description
Background: Dendritic cells (DCs) are critical for regulating CD4 and CD8 T cell immunity, controlling Th1, Th2, and Th17 bias, generating inducible Tregs, and inducing tolerance. Multiple DC subsets have been identified in the mouse that are thought to have evolved to control these different immune outcomes. However, how these subsets differentially respond to inflammatory and/or tolerogenic signals in order to accomplish their divergent functionality remains unclear. Results: We analysed the responses of murine, splenic CD8 and CD11b DC subsets to in-vivo stimulation with lipopolysaccharide using RNA-Seq and systems biology approaches and observed responses are highly subset-specific. We reanalysed multiple datasets from the literature and show that these subset responses are obscured when analysing signaling at the population level. We show that the subset-specificity is due to the unique regulation of distinct TLR4 pathway modulators that ‘fine-tune’ a common TLR4 cascade rather and not due to major differences in signaling pathways or transcription factors. Conclusions: We propose the Pathway Modulation Model wherein common signaling pathways are regulated by unique sets of modulators allowing for distinct immune responses in closely related DC subsets. We extend these observations using analagous datasets from the literature and show that our model provides a global mechanism for generating cell subset-specific signaling in multiple subpopulations in mouse and man. Splenic CD8 and CD11b DC subsets from LPS stimulated (10 pooled animals) and Control (5 pooled animals) mice were analysed by RNA-Seq.
Experiment type
RNA-seq of coding RNA 
Contacts
David Graeme Hancock <davidh@centenary.org.au>, Barbara Fazekas de St Groth, Chris D Fjell, David G Hancock, Elena Shklovskaya, Reza Falsafi, Robert E Hancock, Thomas V Guy, William Ritchie
Citation
A Systems Biology Approach to the Analysis of Subset-Specific Responses to Lipopolysaccharide in Dendritic Cells. Hancock DG, Shklovskaya E, Guy TV, Falsafi R, Fjell CD, Ritchie W, Hancock RE, Fazekas de St Groth B. , PMID:24949855
MINSEQE
Exp. designProtocolsVariablesProcessedSeq. reads
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