Cellular Decision Making by Non-Integrative Processing of TLR Inputs

Publication date: 4 April 2017
Source:Cell Reports, Volume 19, Issue 1
Author(s): Ryan A. Kellogg, Chengzhe Tian, Martin Etzrodt, Savaş Tay
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.

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Teaser

Kellogg et al. study NF-κB responses under TLR co-stimulation and observe that single cells respond with a dynamic NF-κB profile characteristic of either TLR2 or TLR4 activation, rather than a mixed response. Modeling and microfluidic experiments revealed that switch-like NF-κB activation and TLR cross-tolerance mediate this phenomenon, termed non-integrative processing.


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