Distinct NF-κB and MAPK Activation Thresholds Uncouple Steady-State Microbe Sensing from Anti-pathogen Inflammatory Responses
Gottschalk RA, Martins AJ, Angermann BR, Dutta B, Ng CE, Uderhardt S, Tsang JS, Fraser IDC, Meier-Schellersheim M, Germain RN (2016)
Publication Type: Journal article
Publication year: 2016
Journal
Book Volume: 2
Pages Range: 378-390
Journal Issue: 6
DOI: 10.1016/j.cels.2016.04.016
Abstract
The innate immune system distinguishes low-level homeostatic microbial stimuli from those of invasive pathogens, yet we lack understanding of how qualitatively similar microbial products yield context-specific macrophage functional responses. Using quantitative approaches, we found that NF-κB and MAPK signaling was activated at different concentrations of a stimulatory TLR4 ligand in both mouse and human macrophages. Above a threshold of ligand, MAPK were activated in a switch-like manner, facilitating production of inflammatory mediators. At ligand concentrations below this threshold, NF-κB signaling occurred, promoting expression of a restricted set of genes and macrophage priming. Among TLR-induced genes, we observed an inverse correlation between MAPK dependence and ligand sensitivity, highlighting the role of this signaling dichotomy in partitioning innate responses downstream of a single receptor. Our study reveals an evolutionarily conserved innate immune response system in which danger discrimination is enforced by distinct thresholds for NF-κB and MAPK activation, which provide sequential barriers to inflammatory mediator production.
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APA:
Gottschalk, R.A., Martins, A.J., Angermann, B.R., Dutta, B., Ng, C.E., Uderhardt, S.,... Germain, R.N. (2016). Distinct NF-κB and MAPK Activation Thresholds Uncouple Steady-State Microbe Sensing from Anti-pathogen Inflammatory Responses. Cell Systems, 2(6), 378-390. https://doi.org/10.1016/j.cels.2016.04.016
MLA:
Gottschalk, Rachel A., et al. "Distinct NF-κB and MAPK Activation Thresholds Uncouple Steady-State Microbe Sensing from Anti-pathogen Inflammatory Responses." Cell Systems 2.6 (2016): 378-390.
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