Hypoxic-ischemic brain injury in neonatal mice sequentially recruits neutrophils with dichotomous phenotype and function
Neonatal encephalopathy caused by hypoxia-ischemia (HI) leads to a strong neutrophil infiltration. The long-held assumption that neutrophils act exclusively as tissue-damaging cells, is challenged by increasing evidence of a profound neutrophil heterogeneity. Here, we uncovered a pronounced phenotypical and functional diversification of neutrophils in neonatal mice depending on the disease stage. Neutrophil infiltration was biphasic, peaking 1 and 7 days after HI. Early brain-infiltrating neutrophils displayed a hyperactivated phenotype, whereas neutrophils at day 7 exhibited an angiogenic phenotype with high Siglec-F expression. Acute neutrophil depletion protected against neural cell death, associated with decreased hyperactivity in adolescent animals. Delayed neutrophil depletion impaired vascular and oligodendrocyte regeneration, resulting in exacerbated alterations of anxiety-related behavior and myelination deficits. These findings suggest a divergent function of neutrophils, with early neutrophils aggravating tissue damage and late neutrophils contributing to neurological recovery. The disease stage-dependent neutrophil diversification offers new possibilities to identify disease-stage-specific therapeutic targets.
Authors
- Mathis Richter (ORCID: https://orcid.org/0000-0002-3110-6137)
- Alexa Josephine Fischer
- Josephine Herz (ORCID: https://orcid.org/0000-0001-8132-7459)
- Oliver Soehnlein (ORCID: https://orcid.org/0000-0002-7854-0694)
- Eva Diesterbeck
- Matthias Gunzer (ORCID: https://orcid.org/0000-0002-5534-6055)
- Raphael Chevre (ORCID: https://orcid.org/0000-0002-7564-2919)
- Dirk M. Hermann (ORCID: https://orcid.org/0000-0003-0198-3152)
- Marcel Jung (ORCID: https://orcid.org/0000-0002-8277-3052)
- Christian Köster
- Nina Hagemann (ORCID: https://orcid.org/0000-0002-8098-0402)
- Ursula Felderhoff‐Müser (ORCID: https://orcid.org/0000-0002-7765-8893)
- Nicole Labusek (ORCID: https://orcid.org/0000-0002-1978-6176)
- Jadwiga Jabłońska (ORCID: https://orcid.org/0000-0003-1490-2542)
- C. Joakim Ek (ORCID: https://orcid.org/0000-0002-5764-7679)
- Ivo Bendix (ORCID: https://orcid.org/0000-0002-9751-3640)
- Erik Axel Andersson (ORCID: https://orcid.org/0000-0002-7165-3709)
- Ekaterina Pylaeva (ORCID: https://orcid.org/0000-0002-3941-9664)
- Vikramjeet Singh (ORCID: https://orcid.org/0000-0002-7361-8317)
- Laura Karsch (ORCID: https://orcid.org/0009-0000-4759-9178)
- Dennis Nagel (ORCID: https://orcid.org/0009-0004-2911-9301)
- Marah Sous
Institutions
- German Cancer Research Center (DE)
- University of Münster (DE)
- Essen University Hospital (DE)
- Leibniz Institute for Analytical Sciences - ISAS (DE)
- Wallenberg Wood Science Center (SE)
- West German Heart and Vascular Center Essen (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- University of Duisburg-Essen (DE)
- University of Gothenburg (SE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-03
- DOI
- https://doi.org/10.1038/s41467-025-65517-1
- Citations
- 3
- Primary Topic
- Neonatal and fetal brain pathology
- Type
- article
- Field-Weighted Citation Impact
- 10.48