A circadian checkpoint relocates neutrophils to minimize injury
Inflammation-driven injury, a significant source of morbidity and mortality worldwide, is largely mediated by the cytotoxic activities of neutrophils, which extend the initial lesion and jeopardize organ function. Intriguingly, inflammatory injury naturally declines at specific times of day, suggesting that circadian mechanisms exist that mitigate the destructive activity of neutrophils and protect the host. Here, we show that the periods of diurnal protection coincide with peaks in plasma CXCL12, a chemokine that inhibits the neutrophil-intrinsic circadian clock by signaling through CXCR4. Genetic deletion of this clock, or a hyperactive form of CXCR4, prevented the diurnal spikes of injury, and treatment with a synthetic CXCR4 agonist conferred protection from myocardial and vascular injury. In tissues, this protection was mediated by repositioning neutrophils in the wound core, which spared neighboring host cells from apoptotic death. Thus, a circadian neutrophil checkpoint protects from exuberant inflammation and can be activated to protect the host.
Authors
- Miguel Molina-Moreno (ORCID: https://orcid.org/0000-0002-3493-7470)
- Jon Sicilia (ORCID: https://orcid.org/0000-0002-5073-9132)
- José M. Adrover (ORCID: https://orcid.org/0000-0002-1395-5477)
- Vanessa Núñez (ORCID: https://orcid.org/0000-0002-7473-1514)
- Marı́a A. Moro (ORCID: https://orcid.org/0000-0003-1010-8237)
- María Casanova-Acebes (ORCID: https://orcid.org/0000-0002-5790-1163)
- Jose T. Ortiz‐Pérez (ORCID: https://orcid.org/0000-0001-8043-6055)
- Andrea Rubio-Ponce (ORCID: https://orcid.org/0000-0002-4275-8835)
- Nicolás Rosillo (ORCID: https://orcid.org/0000-0002-4046-8092)
- Kanin Wichapong (ORCID: https://orcid.org/0000-0002-9678-7084)
- Eduardo Peñaloza-Martínez (ORCID: https://orcid.org/0009-0007-1065-9887)
- Georgiana Crainiciuc (ORCID: https://orcid.org/0000-0002-0912-7425)
- Tommaso Vicanolo (ORCID: https://orcid.org/0000-0003-1356-1352)
- David Sancho (ORCID: https://orcid.org/0000-0003-2890-3984)
- Gerry A. F. Nicolaes (ORCID: https://orcid.org/0000-0002-2482-0412)
- Alejandra Aroca-Crevillén (ORCID: https://orcid.org/0000-0002-2481-0863)
- Héctor Bueno (ORCID: https://orcid.org/0000-0003-0277-7596)
- Karl Balabanian (ORCID: https://orcid.org/0000-0002-0534-3198)
- Sandra Martín-Salamanca (ORCID: https://orcid.org/0009-0002-3624-4149)
- Françoise Bachelerie (ORCID: https://orcid.org/0000-0002-0399-3277)
- Lidiane S. Torres (ORCID: https://orcid.org/0000-0002-4598-1899)
- Andrés Hidalgo (ORCID: https://orcid.org/0000-0001-5513-555X)
- Xiaosong Liu (ORCID: https://orcid.org/0009-0006-0620-9341)
Institutions
- Albert Einstein College of Medicine (US)
- Inserm (FR)
- Université Paris Cité (FR)
- Université Paris-Saclay (FR)
- The Francis Crick Institute (GB)
- Yale University (US)
- Maastricht University (NL)
- Research Institute Hospital 12 de Octubre (ES)
- Spanish National Cancer Research Centre (ES)
- Sorbonne Paris Cité (FR)
- Hospital Universitario 12 De Octubre (ES)
- Centro de Investigación Biomédica en Red (ES)
- Hospital Clínic de Barcelona (ES)
- Spanish National Centre for Cardiovascular Research (ES)
- Institut Cochin (FR)
- Fundació Clínic per a la Recerca Biomèdica (ES)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-10-02
- DOI
- https://doi.org/10.1084/jem.20250240
- Citations
- 2
- Primary Topic
- Circadian rhythm and melatonin
- Type
- article
- Field-Weighted Citation Impact
- 1.83