Vicanolo, TommasoÖzcan, AlazLi, Jackson LiangYaoHuerta-López, CarlaBallesteros, IvánRubio-Ponce, AndreaDumitru, Andra CNicolás-Ávila, Jose ÁngelMolina-Moreno, MiguelReyes-Gutierrez, PabloJohnston, Andrew DMartone, CatherineGreto, EricQuílez-Alvarez, AntonioCalvo, EnriqueBonzon-Kulichenko, ElenaÁlvarez-Velez, RebecaChooi, Ming YaoKwok, ImmanuelGonzález-Bermúdez, BlancaMalleret, BenoitEspinosa, Francisco MZhang, MingWang, Yu-LongSun, DashengZhen Chong, ShuEl-Armouche, AliKim, Kevin KUdalova, Irina AGreco, ValentinaGarcia, RicardoVázquez, JesúsDopazo, AnaPlaza, Gustavo RAlegre-Cebollada, JorgeUderhardt, StefanNg, Lai GuanHidalgo, Andrés2025-12-112025-12-112025-05Nature. 2025 May;641(8063):740-748.https://hdl.handle.net/20.500.12105/27011Defence from environmental threats is provided by physical barriers that confer mechanical protection and prevent the entry of microorganisms. If microorganisms overcome those barriers, however, innate immune cells use toxic chemicals to kill the invading cells. Here we examine immune diversity across tissues and identify a population of neutrophils in the skin that expresses a broad repertoire of proteins and enzymes needed to build the extracellular matrix. In the naive skin, these matrix-producing neutrophils contribute to the composition and structure of the extracellular matrix, reinforce its mechanical properties and promote barrier function. After injury, these neutrophils build 'rings' of matrix around wounds, which shield against foreign molecules and bacteria. This structural program relies on TGFβ signalling; disabling the TGFβ receptor in neutrophils impaired ring formation around wounds and facilitated bacterial invasion. We infer that the innate immune system has evolved diverse strategies for defence, including one that physically shields the host from the outside world.We thank M. Dueñas, L. Montesino, M. Vara, J. Nieto, Y. Qian, T. Khoyratty, S. Callejas, D. Cibrián and L. Morales for technical and analytical support with NanoString analysis, biomechanical and proteomic experiments; members of the A.H. laboratory for animal husbandry and discussion; the SIgN mouse core facility for technical help and support; the SIgN flow cytometry team for assistance with cell sorting; the SIgN functional genomics and SIgN computational immunology team (N. Ang, L. M. Chan and D. Kaibo) for expertise on and assistance with transcriptomics; D. Lopez for help with the infection experiments; and the Center for Cellular and Molecular Imaging, Electron Microscopy Facility at Yale Medical School for assistance. C. J. Yu-Shen provided material assistance with our in vitro bacterial killing assays. Dr. Mück-Häusl and Dr. Rinkevich at Helmholtz Zentrum München for help designing the CNA35-reporter mice. T.V. received the support of a fellowship from La Caixa Foundation (ID 100010434) with fellowship code LCF/BQ/DR21/11880022 and from Boehringer Ingelheim Fonds; A.Ö. was supported by the Swiss National Science Foundation (P500PB-206852); J.A.N.-A. was supported by fellowship SVP-2014-068595; J.L.L. was supported by A*STAR and a Juan de la Cierva JCI-2017-33136 fellowship from Ministerio de Ciencia e Innovación (MCIN); C.H.-L. was the recipient of an FPI predoctoral fellowship (BES-2015-073191); A.C.D. was supported by a Marie Curie Individual Fellowship DILEMMA 101065552 and from La Caixa Foundation (ID 100010434) under the agreement LCF/BQ/PI22/ 11910029; A.H. was supported by grant R01AI165661 from the NIH/NIAD, RTI2018-095497- B-I00 from MCIN, HR17_00527 from Fundación La Caixa, the Transatlantic Network of Excellence (TNE-18CVD04) from the Leducq Foundation, and FET-OPEN (no. 861878) from the European Commission; L.G.N. was supported by the Ministry of Science and Technology of China (grant 2023YFC2306302) and the National Natural Science Foundation of China (grants W2431020 and 92374205); G.R.P., R.G. and J.A.-C. were supported by Grant Tec4Bio-CM/P2018/NMT-4443 from the Comunidad de Madrid; K.K.K. was supported by grants NHLBI R01HL156998 and NHLBI R01HL153056 from the NIH; I.A.U. was supported by the Wellcome Trust Investigator Award 209422/Z/17/Z; J.V. was supported by grants PGC2018-097019-B-I00 and PID2021-122348NB-I00 from MCIN, and HR17-00247 and HR22/52420019 from Fundación La Caixa; S.U. was supported by the Hightech Agenda Bayern, the European Research Council (101039438) and the Deutsche orschungsgesellschaft (DFG; 447268119, 448121430 and 405969122); I.B. was supported by grants from MCIN (RYC2020-029563-I and PID2022-140534NB-I00); and J.L.L and S.Z.C. were supported by the Singapore Immunology Network (SIgN) and the Agency for Science, Technology and Research (A*STAR). Volumetric imaging was performed at the Optical Imaging Centre Erlangen (OICE, FAU) funded by DFG (project 261193037). The CNIC is supported by the MCIN and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (CEX2020-001041-S).engAMhttp://creativecommons.org/licenses/by-nc-nd/4.0/Attribution-NonCommercial-NoDerivatives 4.0 International40108463641(8063)740-748NATUREopen access