
Open access
Date
2017-04Type
- Journal Article
Citations
Cited 29 times in
Web of Science
Cited 31 times in
Scopus
ETH Bibliography
yes
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Abstract
Cells receive a multitude of signals from the environment, but how they process simultaneous signaling inputs is not well understood. Response to infection, for example, involves parallel activation of multiple Toll-like receptors (TLRs) that converge on the nuclear factor κB (NF-κB) pathway. Although we increasingly understand inflammatory responses for isolated signals, it is not clear how cells process multiple signals that co-occur in physiological settings. We therefore examined a bacterial infection scenario involving co-stimulation of TLR4 and TLR2. Independent stimulation of these receptors induced distinct NF-κB dynamic profiles, although surprisingly, under co-stimulation, single cells continued to show ligand-specific dynamic responses characteristic of TLR2 or TLR4 signaling rather than a mixed response, comprising a cellular decision that we term “non-integrative” processing. Iterating modeling and microfluidic experiments revealed that non-integrative processing occurred through interaction of switch-like NF-κB activation, receptor-specific processing timescales, cell-to-cell variability, and TLR cross-tolerance mediated by multilayer negative feedback. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000130292Publication status
publishedExternal links
Journal / series
Cell ReportsVolume
Pages / Article No.
Publisher
ElsevierSubject
Digital; Dynamics; Immunity; Information processing; Live-cell imaging; Microfluidics; Signaling; Single cell; Synergy; toll-like receptorsMore
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Citations
Cited 29 times in
Web of Science
Cited 31 times in
Scopus
ETH Bibliography
yes
Altmetrics