Journal Article

DKFZ-2025-02270

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Hypoxic-ischemic brain injury in neonatal mice sequentially recruits neutrophils with dichotomous phenotype and function.

Richter, M. ; Diesterbeck, E. ; Pylaeva, E.DKFZ* ; Labusek, N. ; Köster, C. ; Nagel, D. ; Karsch, L. ; Fischer, A. J. ; Sous, M. ; Jung, M. ; Chevre, R. ; Hagemann, N. ; Andersson, E. A. ; Ek, C. J. ; Singh, V. ; Hermann, D. M. ; Gunzer, M. ; Jablonska, J.DKFZ* ; Felderhoff-Müser, U. ; Bendix, I. ; Soehnlein, O. ; Herz, J.

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-65517-1

Abstract: 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.

Keyword(s): Animals (MeSH) ; Hypoxia-Ischemia, Brain: immunology (MeSH) ; Hypoxia-Ischemia, Brain: pathology (MeSH) ; Hypoxia-Ischemia, Brain: physiopathology (MeSH) ; Neutrophils: immunology (MeSH) ; Neutrophils: metabolism (MeSH) ; Neutrophils: pathology (MeSH) ; Animals, Newborn (MeSH) ; Phenotype (MeSH) ; Mice (MeSH) ; Neutrophil Infiltration (MeSH) ; Mice, Inbred C57BL (MeSH) ; Brain: pathology (MeSH) ; Brain: immunology (MeSH) ; Oligodendroglia: pathology (MeSH) ; Male (MeSH) ; Disease Models, Animal (MeSH)

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Essen/Düsseldorf (ED01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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