Contextual Control of TLR-induced Responses by Divergent Signaling Thresholds

Authors

• RA Gottschalk
• AJ Martins
• BR Angermann
• B Dutta
• CE Ng
• S Uderhardt
• JS Tsang
• IDC Fraser
• M Meier-Schellersheim
• RN Germain

Abstract

The innate immune system generates context-specific responses to microbial products, distinguishing steady-state stimuli from those of invasive pathogens. To date, we lack a detailed mechanistic understanding of the signaling logic that limits inflammatory cytokine production to non-dangerous inputs, thereby avoiding immunopathology. Using single cell quantitative assays and computational modeling, we found multiple thresholds for signaling pathways dictating stimulus-dependent functionality in macrophages exposed to TLR4 ligand. While TNF protein expression was controlled by switch-like MAPK activation, NF-κB activity occurred at ligand concentrations below the MAPK-mediated threshold for inflammatory cytokine production, and primed cells for a more robust response to subsequent stimulation. Remarkably, macrophages from distinct mouse strains and from multiple human donors showed quantitatively very similar behavior. Our study thus reveals a tightly regulated ‘low-noise robust response’ system, which modeling suggests can be disturbed by small expression variations in regulatory phosphatases, including those showing linkage to human inflammatory diseases.

Scientific Focus Area: Immunology

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