Architecture of the neutrophil compartment

Architecture of the neutrophil compartment

Nature

10.1038/s41586-025-09807-0

https://doi.org/10.1038/s41586-025-09807-0

Daniela Cerezo-Wallis, Andrea Rubio-Ponce, Mathis Richter, Emanuele Pitino, Immanuel Kwok, Giovanni Marteletto, Ana Cristina Guanolema-Coba, Changming Shih, Run-Kai Huang, Ana Moraga, Natalia Borbaran Bravo, Samuel Doré, Sergio Callejas, David G. Aragonés, Daniel Jiménez-Carretero, Daniel Martin, Samuel Ovadia, Tommaso Vicanolo, Georgiana Crainiciuc, Jon Sicilia, Tong Deng, Anjelica Martin, Jing Zhang, Maria Isabel Cuartero, Diego Moncada Giraldo, Alicia Garcia-Culebras, Alejandra Aroca-Crevillen, Sandra Martín-Salamanca, Carlos Torroja, Max Ruiz, Irene Ruano, Melissa S. F. Ng, Jian Hou, You Wang, Ming Zhang, Jun Pu, Ana Herruzo, David Chang van Oordt, Seokyoon Chang, Alexander E. Downie, Fei Chen, Andrea L. Graham, William C. Gause, Pierre O. Fiset, Jonathan D. Spicer, Holger Heyn, Maria A. Zuriaga, Juan A. Bernal, Irina A. Udalova, Maria A. Moro, Katrien de Bock, Ana Dopazo, Jose J. Fuster, Fátima Sánchez-Cabo, Juan C. Nieto, Gabriel F. Calvo, Julia Skokowa, Oliver Soehnlein, Daniela F. Quail, Logan A. Walsh, Lai Guan Ng, Andrés Hidalgo, Iván Ballesteros

03 December 2025

Cerezo-Wallis, D., Rubio-Ponce, A., Richter, M., Pitino, E., Kwok, I., Marteletto, G., Guanolema-Coba, A. C., Shih, C., Huang, R.-K., Moraga, A., Bravo, N. B., Doré, S., Callejas, S., Aragonés, D. G., Jiménez-Carretero, D., Martin, D., Ovadia, S., Vicanolo, T., Crainiciuc, G., … Ballesteros, I. (2025). Architecture of the neutrophil compartment. Nature. https://doi.org/10.1038/s41586-025-09807-0

Neutrophils exhibit remarkable phenotypic and functional diversity across tissues and diseases1,2, yet the lack of understanding of how this immune compartment is globally organized challenges translation to the clinic. Here we performed single-cell transcriptional profiling of neutrophils spanning 47 anatomical, physiological and pathological scenarios to generate an integrated map of the global neutrophil compartment in mice, which we refer to as NeuMap. NeuMap integrates and expands existing models3,4 to generate fundamental new insights; it reveals that neutrophils organize in a finite number of functional hubs that distribute sequentially during maturation to then branch out into interferon-responsive a­ nd i­ mm­ un­ os­ up­ pr­ essive states, as well as a functionally silent state that dominates in the healthy circulation. Computational modelling and timestamp analyses identify prototypical trajectories that connect these hubs, and reveal that the dynamics and preferred paths vary during health, inflammation and cancer. We show that TGFβ, IFNβ and GM-CSF push neutrophils along the different trajectories, and projection of chromatin accessibility sites onto NeuMap reveals that the transcription factor JUNB controls angiogenic and immunosuppressive states and promotes tissue revascularization. The architecture of NeuMap appears to be conserved across sex, environmental and genetic backgrounds, as well as in humans. Finally, we show that NeuMap enables inference of t­ he p­ at­ hophysiological state of the host by profiling blood neutrophils. Our study delineates the global architecture of the neutrophil compartment and establishes a framework for exploration and exploitation of neutrophil biology.

Publisher Copyright

This research / project is supported by the Ministry of Health National Medical Research Council - Open Fund - Young Individual Research Grant
Grant Reference no. : MOH-OFYIRG24jan-0032

This is a post-peer-review, pre-copyedit version of an article published in Nature. The final authenticated version is available online at: https://doi.org/10.1038/s41586-025-09807-0

https://oar.a-star.edu.sg/communities-collections/articles/22667

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1476-4687

Singapore Immunology Network