Neutrophil dynamics, plasticity and function in acute neurodegeneration following neonatal hypoxia–ischemia

• Published in: Brain, behavior, and immunity Vol. 92; pp. 234 - 244
• Main Authors: Mülling, Kerstin, Fischer, Alexa Josephine, Siakaeva, Elena, Richter, Mathis, Bordbari, Sharareh, Spyra, Ilona, Köster, Christian, Hermann, Dirk M., Gunzer, Matthias, Felderhoff-Müser, Ursula, Bendix, Ivo, Jablonska, Jadwiga, Herz, Josephine
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.02.2021
• Subjects: Brain ischemia; Ly6G; Neonatal hypoxia–ischemia; Neutrophils; Brain ischemia; Ly6G; Neonatal hypoxia–ischemia; Neutrophils
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2020.12.012

•HI-induced peripheral neutrophilia precedes neutrophil infiltration into the brain.•Neonatal neutrophils are rapidly activated in the injured hypoxic-ischemic brain.•Post-hypoxic neutrophil depletion with anti-Ly6G protects from early neurodegeneration.•Neuroprotection by anti-Ly6G is associated with reduced astro- and microgliosis. Neonatal encephalopathy following hypoxia–ischemia (HI) is a major cause of long-term morbidity and mortality in children. Even though HI-induced neuroinflammation, involving infiltration of peripheral immune cells into the CNS has been associated with disease pathogenesis, the specific role of neutrophils is highly debated. Due to immaturity of the neonatal immune system, it has been assumed that neutrophils are less clinically relevant in neonatal HI-induced brain injury. In the present study, we demonstrate that neutrophils are rapidly activated in the neonatal brain after exposure to experimental HI, revealed by an enhanced proportion of CD86+ cells and an increased expression of CD11b compared to splenic and blood neutrophils. Furthermore, production of reactive oxygen species and the proportion of hyperactivated/aged (CXCR4+CD62L−) cells was enhanced in brain compared to peripheral neutrophils. Delayed neutrophil depletion, initiated 12 h after HI resulted in reduced cellular neurodegeneration, associated with reduced micro- and astroglial activation. In the present study, we uncovered a new complex switch of the phenotype in brain neutrophils, which may offer new possibilities for the development of selective therapeutic approaches by modulation of neutrophils in the early post-hypoxic disease phase.