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 Jabłońska, Ursula Felderhoff‐Müser, Ivo Bendix, Oliver Soehnlein, Josephine Herz
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.