Agent-based modeling identifies multiple paths for inflammation resolution.

SUMMARY: Sterile inflammation emerges from spatially coordinated interactions between immune recruitment, polarization, signal diffusion, and tissue turnover. Capturing this complexity requires modeling frameworks that integrate stochasticity, spatial heterogeneity, and functional redundancy across immune cell types. We present a spatially explicit agent-based model of sterile inflammation based on a functional mono-agent abstraction, in which immune cells share core capabilities, e.g. polarization, chemotaxis, signal production, and phagocytosis, while differing through parameterization rather than rigid rule sets. Using large-scale global parameter exploration via Latin Hypercube Sampling, we generated 300 000 simulations to characterize the model's dynamical landscape. Dimensionality reduction suggested a continuous manifold of inflammatory trajectories. Applying biologically informed temporal criteria identified a highly constrained subspace consistent with canonical sterile inflammation. Within this region, multiple distinct yet self-consistent, kinetic regimes achieved successful resolution. These results indicate that sterile inflammation is not a single dynamical attractor but an emergent coordination constraint in a high-dimensional functional space, providing a systems-level framework for exploring immune regulation and dysregulation.

AVAILABILITY AND IMPLEMENTATION: Model can be found as a demo on ISiCell website at https://isicell.irit.fr/app.html.