title: Cellular Decision Making by Non-Integrative Processing of TLR Inputs.
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.
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zürich 4058, Switzerland; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Kellogg
authors.affiliation: Niels Bohr Institute, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Chengzhe
authors.initials: C
authors.lastname: Tian
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zürich 4058, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Etzrodt
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zürich 4058, Switzerland; Institute for Molecular Engineering, University of Chicago, Chicago, IL 60637, USA; Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL 60637, USA. Electronic address: tays@uchicago.edu.
authors.forename: Savaş
authors.initials: S
authors.lastname: Tay
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001424:Bacterial Infections / Q000378:metabolism; D002450:Cell Communication; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D055666:Lipopeptides / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D046210:Microfluidic Analytical Techniques; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D055666:Lipopeptides; D008070:Lipopolysaccharides; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; C508075:Pam(3)CSK(4) peptide; D048029:TNF Receptor-Associated Factor 6; C000604754:Tifab protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4
keywords: digital; dynamics; immunity; information processing; live-cell imaging; microfluidics; signaling; single cell; synergy; toll-like receptors