title: Distinct NF-κB and MAPK Activation Thresholds Uncouple Steady-State Microbe Sensing from Anti-pathogen Inflammatory Responses.
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.
authors.affiliation: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: gottschalkra@niaid.nih.gov.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Gottschalk
authors.affiliation: Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Martins
authors.affiliation: Computational Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Bastian R
authors.initials: BR
authors.lastname: Angermann
authors.affiliation: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Dutta
authors.affiliation: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Caleb E
authors.initials: CE
authors.lastname: Ng
authors.affiliation: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Uderhardt
authors.affiliation: Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Tsang
authors.affiliation: Signaling Systems Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Iain D C
authors.initials: ID
authors.lastname: Fraser
authors.affiliation: Computational Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Meier-Schellersheim
authors.affiliation: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: rgermain@niaid.nih.gov.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Germain
mesh_terms: D000818:Animals; D016207:Cytokines; D004789:Enzyme Activation; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation; D008070:Lipopolysaccharides; D020935:MAP Kinase Signaling System; D008264:Macrophages; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D020928:Mitogen-Activated Protein Kinases