ArticleCell systems2016
Distinct NF-κB and MAPK Activation Thresholds Uncouple Steady-State Microbe Sensing from Anti-pathogen Inflammatory Responses.
Article in Cell systems, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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Who cites it
70 citing papers in PubMed, 107 citations in OpenAlex.
- Wood Smoke Exposure Alters Human Inflammatory Responses to Viral Infection in a Sex-Specific Manner. A Randomized, Placebo-controlled Study.American journal of respiratory and critical care medicine · 2019Trial
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- Dissection of MAPK and NF-κB p65 signaling dynamics underlying LPS tolerance in macrophages at the single-cell level.Biotechnology reports (Amsterdam, Netherlands) · 2026Article
- The theory of the inflammatory ecosystem.Science China. Life sciences · 2026Review
- Immunomodulatory Effects of Bifidobacterium bifidum BGN4 in Cyclophosphamide-induced Immunosuppressed Mice via Activation of NK Cells and Macrophages.Probiotics and antimicrobial proteins · 2026Article
- Quantitative Modeling of TLR Signaling Reveals Missing Negative Feedback Guiding Identification of TANK-IKKε Checkpoint.bioRxiv : the preprint server for biology · 2026Article
- Macrophages tune responses to pathogen dynamics through TLR4 stimulation memory and by licensing susceptibility to IL-10.bioRxiv : the preprint server for biology · 2026Article
- Editorial for the Special Issue "The Role of Bioactives in Inflammation, 2nd Edition".Current issues in molecular biology · 2026Article
- From Trait-Structured Within-Host Dynamics to SIR Models: A Multiscale Framework With Re-Exposure.Bulletin of mathematical biology · 2026Article
- Optimising the induction of inflammation within preterm infant-derived intestinal epithelial organoids.Npj gut and liver · 2026Article
- An NF-kB/TNF-alpha signalling feedback loop acts to coordinate tissue regeneration and macrophage behaviour in zebrafish.NPJ Regenerative medicine · 2025Article
- Article
- Imaging flow cytometry-based cellular screening elucidates pathophysiology in individuals with Variants of Uncertain Significance.Genome medicine · 2025Article
- Cellular defense mechanisms against asbestos fibers.Frontiers in public health · 2025Review
- Article
- Intersection of inflammation and viral replication: the central role of MAPK signaling in viral respiratory infections.Frontiers in microbiology · 2025Review
- Bactericidal antibiotic treatment induces damaging inflammation via TLR9 sensing of bacterial DNA.Nature communications · 2024Article
- Prior Fc receptor activation primes macrophages for increased sensitivity to IgG via long-term and short-term mechanisms.Developmental cell · 2024Article
- Dynamical and combinatorial coding by MAPK p38 and NFκB in the inflammatory response of macrophages.Molecular systems biology · 2024Article
- Platelet transcription factors license the pro-inflammatory cytokine response of human monocytes.EMBO molecular medicine · 2024Article
10 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.