Modeling heterogeneous signaling dynamics of macrophages reveals principles of information transmission in stimulus responses

Xiaolu Guo, Adewunmi Adelaja, Apeksha Singh, Roy Wollman and Alexander Hoffmann ()
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Xiaolu Guo: University of California Los Angeles
Adewunmi Adelaja: University of California Los Angeles
Apeksha Singh: University of California Los Angeles
Roy Wollman: University of California Los Angeles
Alexander Hoffmann: University of California Los Angeles

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Macrophages initiate pathogen-appropriate immune responses with the activation dynamics of transcription factor NFκB mediating specificity. Live-cell imaging revealed the stimulus-response specificity of NFκB dynamics among populations of heterogeneous cells. To study stimulus-response specificity beyond what is experimentally accessible, we develop mathematical model simulations that capture the heterogeneity of stimulus-responsive NFκB dynamics and the stimulus-response specificity performance of the population. Complementing experimental data, extended-dose response simulations improved channel capacity estimates. By collapsing parameter distributions, we locate information loss to receptor modules, while the negative-feedback-containing core module shows remarkable signaling fidelity. Further, constructing virtual single-cell networks reveals the stimulus-response specificity of single cells. We find that despite stimulus-response specificity 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.

Date: 2025
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DOI: 10.1038/s41467-025-60901-3

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