Hypoxic-ischemic brain injury in neonatal mice sequentially recruits neutrophils with dichotomous phenotype and function
- Mathis Richter
- Eva Diesterbeck
- Ekaterina Pylaeva
- Nicole Labusek
- Christian Köster
- Dennis Nagel
- Laura Karsch
- Alexa Josephine Fischer
- Marah Sous
- Marcel Jung
- Raphael Chevre
- Nina Hagemann
- Erik Axel Andersson
- C. Joakim Ek
- Vikramjeet Singh
- Dirk M. Hermann
- Matthias Gunzer
- Jadwiga Jablonska
- Ursula Felderhoff-Müser
- Ivo Bendix
- Oliver Soehnlein
- Josephine Herz
2025-11-03
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.