Modeling single-cell heterogeneity in signaling dynamics of macrophages reveals principles of information transmission

Macrophages initiate pathogen-appropriate immune responses with the
activation dynamics of transcription factor NFκB mediating specificity.
Live-cell imaging revealed the stimulus-response specificity (SRS) of NFκB
dynamics among heterogeneous populations of cells. To study SRS beyond
what is experimentally accessible, we developed mathematical model
simulations that capture the cellular heterogeneity of stimulus-responsive
NFκB dynamics and the SRS performance of the population. Complementing
experimental data, extended-dose response simulations improved channel
capacity estimates. By collapsing parameter distributions, we located
information loss to receptor modules, while the
negative-feedback-containing core module showed remarkable signaling
fidelity. Further, constructing single-cell network models revealed the
stimulus-response specificity of single cells (scSRS). We found that
despite SRS limitations at the population level, the majority of single
cells are capable of responding specifically to immune threats, and that
the few instances of stimulus-pair confusion are highly uncorrelated. The
diversity of “blindspots” enable small consortia of macrophages to achieve
perfect stimulus distinction.