Behavioral Immune Landscapes of Inflammation

Abstract

Transcriptional or proteomic profiling of individual cells have revolutionized interpretation of biological phenomena by providing cellular landscapes of healthy and diseased tissues. These approaches, however, fail to describe dynamic scenarios in which cells continuously change their biochemical properties and downstream “behavioral” outputs. Here, we used 4D live imaging to record tens to hundreds of morpho-kinetic parameters describing the dynamism of individual leukocytes at sites of active inflammation. By analyzing >100,000 reconstructions of cell shapes and tracks over time, we obtained behavioral descriptors of individual cells and used these high-dimensional datasets to build behavioral landscapes. These landscapes recognized leukocyte identities in the inflamed skin and trachea, and inside blood vessels uncovered a continuum of neutrophil states, including a large, sessile state that was embraced by the underlying endothelium and associated with pathogenic inflammation. Behavioral screening in mouse mutants identified the kinase Fgr as a driver of this pathogenic state, and interference of Fgr protected from inflammatory injury. Thus, behavioral landscapes report distinct properties of dynamic environments at high cellular resolution.