Linking Systemic Endotoxin Exposure to Retinal Microglia Migration Through Mathematical Modeling

Abstract

Microglia are the resident immune cells of the central nervous system (CNS), including the brain, spinal cord, and retina, where they serve as the first line of defense against infection and inflammation. Dys-regulated microglia activity has been implicated in vision-threatening diseases, highlighting the need to understand how retinal microglia respond to inflammatory stimuli. Importantly, acute inflammation induces substantial redistribution of microglia across retinal layers, yet the mechanisms governing this migration remain poorly understood. Here, we develop the first mathematical model of retinal microglia migration during inflammation to determine how inflammatory exposure, administration route, and species-specific pharmacokinetics shape redistribution dynamics across the retina. The model couples lipopolysaccharide (LPS) pharmacokinetics with microglia migration between the outer plexiform layer (OPL), inner plexiform layer (IPL), and ganglion cell layer/nerve fiber layer (GCL/NFL). Model parameters are calibrated to retinal microglia density measurements from mice following LPS (bacterial endotoxin) challenge, before extending the framework to rats and rhesus macaques to investigate species-specific responses. Simulations also compare how administration route, i.e. intravenous or intraperitoneal injections, alter retinal LPS exposure and subsequent microglia redistribution. Our results suggest that redistribution patterns are driven primarily by LPS delivery route and species-specific pharmacokinetics, rather than the initial microglia distribution across retinal layers. Together, these findings provide new insight into immune cell reorganization in the inflamed retina and demonstrate how mechanistic mathematical modeling can be adapted across experimental designs, administration routes, and animal species.