TY - JOUR
T1 - Behavioural immune landscapes of inflammation
AU - Crainiciuc, Georgiana
AU - Palomino-Segura, Miguel
AU - Molina-Moreno, Miguel
AU - Sicilia, Jon
AU - Aragones, David G.
AU - Li, Jackson Liang Yao
AU - Madurga, Rodrigo
AU - Adrover, José M.
AU - Aroca-Crevillén, Alejandra
AU - Martin-Salamanca, Sandra
AU - del Valle, Alfonso Serrano
AU - Castillo, Sandra D.
AU - Welch, Heidi C.E.
AU - Soehnlein, Oliver
AU - Graupera, Mariona
AU - Sánchez-Cabo, Fátima
AU - Zarbock, Alexander
AU - Smithgall, Thomas E.
AU - Di Pilato, Mauro
AU - Mempel, Thorsten R.
AU - Tharaux, Pierre Louis
AU - González, Santiago F.
AU - Ayuso-Sacido, Angel
AU - Ng, Lai Guan
AU - Calvo, Gabriel F.
AU - González-Díaz, Iván
AU - Díaz-de-María, Fernando
AU - Hidalgo, Andrés
N1 - Funding Information:
Acknowledgements We thank all members of the Hidalgo laboratory and M. Desco for discussion; P. Frenette for inspiring this study; C. C. Goh and E. Y. Kim for seeding imaging experiments; the electron microscopy unit from the faculty of Medicine of Universidad Autonoma de Madrid for help with experiments; E. Marín, L. Cabezuela, E. Santos, R. Mota and the animal facility at CNIC for animal husbandry, animal procedures and histology; J. Rossaint, M. Gunzer, J.A. Enriquez, A. Mocsai, R.W. Hendricks, G. Sabio, M. Sperandio, E. Hirsch and B. Walzog for the generous gift of mutant mice; and C. Torroja, D. Jiménez and M. Desco for technical advice. This study was supported by RTI2018-095497-B-I00 from Ministerio de Ciencia e Innovación (MCIN), HR17_00527 from Fundación La Caixa, Transatlantic Network of Excellence (TNE-18CVD04) from the Leducq Foundation, and FET-OPEN (no. 861878) from the European Commission to A.H. M.P-S. is supported by a Federation of European Biochemical Societies and the EMBO ALTF (no. 1142-2020) long-term fellowships. J.S. is supported by a fellowship (PRE2019-089130) from MICINN and A.A.-C. is supported by fellowship CF/BQ/ DR19/11740022 from La Caixa Foundation. J.L.Y.L. was supported by A*STAR and a Juan de la Cierva JCI-2017-33136 Fellowship from MICINN. S.D.C. is a recipient of a Marie Sklodowska-Curie fellowship (749731). M.G. is supported by SAF2017-89116R-P from MCIN and HR18_00120 from la Fundación La Caixa. T.R.M. is supported by grant NIH AI163223, L.G.N. is supported by SIgN core funding from A*STAR, and G.F.C. is supported by MCIN/ AEI/10.13039/501100011033 (grant PID2019-110895RB-I00) and by Junta de Comunidades de Castilla-La Mancha (SBPLY/19/180501/000211). F.S.-C. is supported by MCIN (grant RTI2018-102084-B-I00), O.S. is supported by the Leducq Foundation (TNE-18CVD04), F.D.-d.-M. is supported by MCIN (TEC2017-84395-P), and T.E.S. is supported by the National Cancer Institute, NIH grant CA233576. The CNIC is supported by the MCIN and the Pro-CNIC Foundation.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/1/20
Y1 - 2022/1/20
N2 - 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’ outputs3–5. 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.
AB - 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’ outputs3–5. 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.
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U2 - 10.1038/s41586-021-04263-y
DO - 10.1038/s41586-021-04263-y
M3 - Article
C2 - 34987220
AN - SCOPUS:85122317973
VL - 601
SP - 415
EP - 421
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7893
ER -