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

Author

Listed:
  • Xiaolu Guo

    (University of California Los Angeles
    University of California Los Angeles)

  • Adewunmi Adelaja

    (University of California Los Angeles
    University of California Los Angeles
    Harvard Combined Dermatology Residency Training Program)

  • Apeksha Singh

    (University of California Los Angeles
    University of California Los Angeles)

  • Roy Wollman

    (University of California Los Angeles
    University of California Los Angeles)

  • Alexander Hoffmann

    (University of California Los Angeles
    University of California Los Angeles)

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.

Suggested Citation

  • Xiaolu Guo & Adewunmi Adelaja & Apeksha Singh & Roy Wollman & Alexander Hoffmann, 2025. "Modeling heterogeneous signaling dynamics of macrophages reveals principles of information transmission in stimulus responses," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60901-3
    DOI: 10.1038/s41467-025-60901-3
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