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Dynamical and combinatorial coding by MAPK p38 and NFκB in the inflammatory response of macrophages

Stefanie Luecke1,2, Xiaolu Guo1,2, Katherine M Sheu1,2

  • 1Department of Microbiology, Immunology, and Molecular Genetics (MIMG), University of California Los Angeles, Los Angeles, CA, 90095, USA.

Molecular Systems Biology
|June 13, 2024
PubMed

Insights

Immune cells use signaling pathway dynamics to identify threats. This study reveals that while p38 signaling distinguishes stimuli, NFκB dynamics are key for encoding information, with combined pathway analysis highlighting specific immune responses.

Area of Science:

  • Immunology
  • Cellular Signaling
  • Systems Biology

Background:

  • Macrophages are crucial for immune responses, sensing pathogens and orchestrating defense mechanisms.
  • Stimulus specificity in immune responses is believed to involve combinatorial and dynamical coding by signaling pathways.
  • While Nuclear Factor kappa B (NFκB) dynamics are known to encode stimulus information, the role of other pathways and their combinatorial coordination remains less understood.

Purpose of the Study:

  • To investigate the interplay between NFκB and p38 signaling pathway dynamics in macrophages upon stimulation.
  • To determine how these dynamics contribute to stimulus specificity and immune response gene expression.
  • To explore the sources and consequences of heterogeneity in these signaling pathways.

Main Methods:

  • Live-cell microscopy was employed to monitor NFκB and p38 dynamics in stimulated macrophages.
  • Information theory and machine learning approaches were used to analyze the signaling dynamics and information encoding.
  • Mathematical modeling and single-cell RNA sequencing (scRNAseq) were utilized to investigate pathway heterogeneity and gene expression variability.

Main Results:

  • p38 signaling dynamics could distinguish between different stimuli (e.g., TNF cytokine vs. pathogen-associated molecular patterns) and doses.
  • p38 dynamics contributed minimally to the information encoded by NFκB dynamics when both pathways were analyzed together.
  • Heterogeneity between NFκB and p38 pathways was largely uncorrelated, potentially arising from branched pathway network topology.
  • Genes regulated by both NFκB and p38 exhibited high variability and bimodality in their expression, as observed in scRNAseq data.

Conclusions:

  • Immune response genes may benefit from decoding either signaling dynamics or combinatorics, but not necessarily both.
  • Uncorrelated heterogeneity in signaling pathways can drive significant gene expression variability.
  • Combinatorial signaling, specifically the interplay of NFκB and p38, acts as a mechanism to restrict the expression of inflammatory cytokines responsive to both pathways to a limited subset of cells.
Keywords:
Combinatorial Signaling DynamicsCytokine ControlInflammationInnate ImmunitySignal Encoding

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