Fig. 3: A dynamical population model explains intracellular and extracellular signaling and regulation.
From: Macrophages employ quorum licensing to regulate collective activation
a The diagram summarizes variables, reactions, and mechanisms in the model of macrophage activation. Symbols: bold non-italicized text for variables; horizontal bars for compartment boundaries; n for nuclear and c for cytoplasmic; asterisks for activated receptors or kinases; delta symbol and circles for perturbation-specific effects; diagonal arrows for a perturbation’s effect; and graphs for time-dependent processes. b Generation of comparable distributions of initial values (data from Supplementary Fig. 2r). The observed distributions in (i) are in non-comparable units. To initiate simulations with NF-κB distributions that vary between high and low cell density and that match experimental observations for EGFP-RelA, we impute from an observed high density distribution (black) a low density distribution (teal) that matches the observed low density distribution (blue). The transform shifts the distribution (ii) and adjusts the proportion of cells in high vs. low states using a Gaussian mixture model of two populations fit to the high density distribution (iii), such that the combined transform (iv) generates an imputed distribution matching the observed low-density distribution (blue) with units relatable to high density (black). c–d Simulated TNF distributions from the calibrated model match experimental trends for cell density and ligand conditions in Fig. 1d, e and BFA conditions in Fig. 1c. All cells have the topology in a and are heterogeneous in initial value and transcription of Rela RNA and initial value of cytoplasmic NF-κB–IκB, derived from b. e–h Comparison of simulated and experimental outcomes for n = 30 cells at high density with sTNFR and LPS treatment. e–f Cumulative total EGFP-RelA (R2 = 0.61, one-tailed permutation test p = 3 × 10−7) and cumulative nuclear EGFP-RelA (R2 = 0.60, one-tailed permutation test p = 4 × 10−7), calculated using time-integrated values. The dotted diagonal is the identity line, and axes are linearly scaled. Color-coding is the same as in Fig. 2c–e. g Coefficient of variation (CV) in mCherry and total EGFP-RelA expression over time. h Trajectories were grouped post hoc by high or low activation. Mean values are in bold. Simulations are shown with and without FBD.
