Gabriel Fernández-Calvo, Florent Ginhoux, Ana Dopazo, Tommaso Vicanolo, Erinke van Grinsven, Eleonora Lusito, Estanislao Nistal-Villán, José M. Adrover, Iván Ballesteros, Giulia Barbiera, Sara González-Hernández, Alberto Benguria, Renato Ostuni, Francisco Mayo, Sandra Martín-Salamanca, Antonio Maccataio, Christian Schulz, Stefanie Ascher, Marco Genua, Juan A. Quintana, Lai Guan Ng, Tariq E. Khoyratty, Fátima Sánchez-Cabo, Irina A. Udalova, Andrés Hidalgo, Alejandra Aroca-Crevillen, Immanuel Kwok, Jackson LiangYao Li, Andrea Rubio-Ponce, Christoph Reinhardt, José Ángel Nicolás-Ávila, Matthias Gunzer, Oliver Soehnlein, Fundación La Marató TV3, Ministerio de Ciencia e Innovación (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Fundación La Caixa, Fondation Leducq, European Research Council, Italian Telethon Foundation, Fondazione Cariplo, German Centre for Cardiovascular Research, Fundación ProCNIC, Junta de Comunidades de Castilla-La Mancha, and BoehingerIngelheim Foundation more...
Classically considered short-lived and purely defensive leukocytes, neutrophils are unique in their fast and moldable response to stimulation. This plastic behavior may underlie variable and even antagonistic functions during inflammation or cancer, yet the full spectrum of neutrophil properties as they enter healthy tissues remains unexplored. Using a new model to track neutrophil fates, we found short but variable lifetimes across multiple tissues. Through analysis of the receptor, transcriptional, and chromatin accessibility landscapes, we identify varying neutrophil states and assign non-canonical functions, including vascular repair and hematopoietic homeostasis. Accordingly, depletion of neutrophils compromised angiogenesis during early age, genotoxic injury, and viral infection, and impaired hematopoietic recovery after irradiation. Neutrophils acquired these properties in target tissues, a process that, in the lungs, occurred in CXCL12-rich areas and relied on CXCR4. Our results reveal that tissues co-opt neutrophils en route for elimination to induce programs that support their physiological demands. This study was supported byIntramural grants from the Severo Ochoa program (IGP-SO), a grant from Fundacio la Marato de TV3 (120/C/2015-20153032), grant SAF2015-65607-R fromMinisterio de Ciencia e Innovacion (MICINN) with co-funding by Fondo Eu-ropeo de Desarrollo Regional (FEDER), RTI2018-095497-B-I00 from MICINN,HR17_00527 from Fundacion La Caixa, and Transatlantic Network of Excel-lence (TNE-18CVD04) from the Leducq Foundation to A.H. I.B. is supportedby fellowship MSCA-IF-EF-748381 and EMBO short-term fellowship 8261.A.R.-P. is supported by a fellowship (BES-2016-076635) and J.A.N.-A. byfellowship SVP-2014-068595 from MICINN. R.O. is supported by ERC startinggrant 759532, Italian Telethon Foundation SR-Tiget grant award F04, ItalianMoH grant GR-201602362156, AIRC MFAG 20247, Cariplo Foundation grant2015-0990, and the EU Infect-ERA 126. C.S. is supported by the SFB 1123,project A07, as well as by the DZHK (German Centre for Cardiovascular Research) and the BMBF (German Ministry of Education and Research) grant81Z0600204. L.G.N. is supported by SIgN core funding from A*STAR. The CNIC is supported by the MICINN and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MICINN award SEV-2015-0505). G.F.-C. issupported by the Spanish Ministerio de Ciencia e Innovacio ́n (grantPID2019-110895RB-100) and Junta de Comunidades de Castilla-La Mancha(grant SBPLY/19/180501/000211). C.R. received funding from the BoehingerIngelheim Foundation (consortium grant ‘‘Novel and Neglected CardiovascularRisk Factors’’) and German Federal Ministry of Education and Research(BMBF 01EO1503) and is a Fellow of the Gutenberg Research College (GFK)at the Johannes Gutenberg-University Mainz Sí more...