Behavioural immune landscapes of inflammation

Crainiciuc, Georgiana; Palomino-Segura, Miguel; Molina-Moreno, Miguel; Sicilia, Jon; Aragones, David G.; Li, Jackson Liang Yao; Madurga, Rodrigo; Adrover, Jose M.; Aroca-Crevillen, Alejandra; Martin-Salamanca, Sandra; Serrano del Valle, Alfonso; Castillo, Sandra D.; Welch, Heidi C. E.; Soehnlein, Oliver; Graupera, Mariona; Sanchez-Cabo, Fatima; Zarbock, Alexander; Smithgall, Thomas E.; Di Pilato, Mauro; Mempel, Thorsten R.; Tharaux, Pierre-Louis; Gonzalez, Santiago F.; Ayuso-Sacido, Angel; Ng, Lai Guan; Calvo, Gabriel F.; Gonzalez-Diaz, Ivan; Diaz-de-Maria, Fernando; Hidalgo, Andres

Zusammenfassung

Transcriptional and proteomic profiling of individual cells have revolutionized interpretation of biological phenomena by providing cellular landscapes of healthy and diseased tissues1,2. These approaches, however, do not describe dynamic scenarios in which cells continuously change their biochemical properties and downstream ‘behavioural’ outputs3,4,5. Here we used 4D live imaging to record tens to hundreds of morpho-kinetic parameters describing the dynamics of individual leukocytes at sites of active inflammation. By analysing more than 100,000 reconstructions of cell shapes and tracks over time, we obtained behavioural descriptors of individual cells and used these high-dimensional datasets to build behavioural landscapes. These landscapes recognized leukocyte identities in the inflamed skin and trachea, and uncovered a continuum of neutrophil states inside blood vessels, including a large, sessile state that was embraced by the underlying endothelium and associated with pathogenic inflammation. Behavioural screening in 24 mouse mutants identified the kinase Fgr as a driver of this pathogenic state, and interference with Fgr protected mice from inflammatory injury. Thus, behavioural landscapes report distinct properties of dynamic environments at high cellular resolution.