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<p>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&#xa0;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • Xiaolu Guo,
  • Adewunmi Adelaja,
  • Apeksha Singh,
  • Roy Wollman,
  • Alexander Hoffmann

摘要

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.