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

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; Jabłońska, Jadwiga; Herz, Josephine

doi:10.1016/j.bbi.2020.12.012

Cited by 27 publications

(33 citation statements)

References 39 publications

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“…Such an interaction regulates neutrophil function in vitro by attenuating neutrophil degranulation, while boosting neutrophil phagocytotic capability and proinflammatory cytokine release, 26 and has recently been indicated to promote astroglia activation in vivo. 27 In contrast, the noninflamed brain of control rats contained quiescent nonreactive astrocytes with low GFAP immunoreactivity, multiple nonoverlapping radial processes within their individual domains, located in the glia limitans, the ventricular walls, and hippocampus. Similarly, in the meninges of infected animals, activation of microglia, identified by Iba1 + immunoreactivity, was identified by cell body hypertrophy and the presence of short, thick processes.…”

Section: S Pneumoniae Infection Promotes Gliosismentioning

confidence: 90%

DNase Treatment Prevents Cerebrospinal Fluid Block in Early Experimental Pneumococcal Meningitis

Pavan

Xavier

Ramos

et al. 2021

Annals of Neurology

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Objective: Streptococcus pneumoniae is the most common cause of bacterial meningitis, a disease that, despite treatment with antibiotics, still is associated with high mortality and morbidity worldwide. Diffuse brain swelling is a leading cause of morbidity in S pneumoniae meningitis. We hypothesized that neutrophil extracellular traps (NETs) disrupt cerebrospinal fluid (CSF) transport by the glymphatic system and contribute to edema formation in S pneumoniae meningitis. Methods: We used DNase I treatment to disrupt NETs and then assessed glymphatic function by cisterna magna injections of CSF tracers in a rat model of S pneumoniae meningitis. Results: Our analysis showed that CSF influx into the brain parenchyma, as well as CSF drainage to the cervical lymph nodes, was significantly reduced in the rat model of S pneumoniae meningitis. Degrading NETs by DNase treatment restored glymphatic transport and eliminated the increase in brain weight in the rats. In contrast, first-line antibiotic treatment had no such effect on restoring fluid dynamics. Interpretation: This study suggests that CSF accumulation is responsible for cerebral edema formation and identifies the glymphatic system and NETs as possible new treatment targets in S pneumoniae meningitis.

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Section: S Pneumoniae Infection Promotes Gliosismentioning

confidence: 90%

DNase Treatment Prevents Cerebrospinal Fluid Block in Early Experimental Pneumococcal Meningitis

Pavan

Xavier

Ramos

et al. 2021

Annals of Neurology

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“…Hypoxic–ischemic brain injury was induced in 9-day-old animals as previously described [ 5 , 9 , 20 , 21 ]. Briefly, the right common carotid artery was occluded through cauterization (high temperature cauter, 1200 °C, Bovie, USA) under isoflurane anesthesia (1.5–2.5 Vol%) followed by 1 h hypoxia (10% O 2 ) in an air-tight oxygen chamber (OxyCycler, Biospherix, USA) after 1 h recovery with their dams.…”

Section: Methodsmentioning

confidence: 99%

“…For evaluation of cellular degeneration, neuronal loss, microglia activation and polarization, 20 µm cryostat sections taken at the hippocampal level (−1.9 to -2.0 mm from bregma) were stained according to our previous reports [ 5 , 9 , 21 ]. Briefly, tissue sections were thawed at 37 °C for 15 min and incubated with 1% BSA, 0.3% cold fish skin gelatin (Sigma Aldrich, Germany) in 1% Tween 20 in Tris-buffered saline (TBS-T) for 1 h at room temperature followed by primary antibody incubation at 4 °C over night.…”

Section: Methodsmentioning

confidence: 99%

“…Cellular degeneration and neuronal loss were quantified in TUNEL and NeuN-stained tissue sections via fluorescence microscopy according to our previous protocols [ 5 , 9 , 21 ]. Nine defined non-overlapping regions of interest (ROI, each 61.220 µm 2 , 3 ROI in the cortex, 3 ROI in the hippocampus and 3 ROI in the thalamus) were visualized by fluorescence microscopy (40 × objective; Axioplan; Zeiss, Germany) connected to a CCD camera (Axiocam ICc1, Zeiss).…”

Section: Methodsmentioning

confidence: 99%

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Hypothermia modulates myeloid cell polarization in neonatal hypoxic–ischemic brain injury

Seitz

Köster

Dzietko

et al. 2021

J Neuroinflammation

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Background Neonatal encephalopathy due to hypoxia–ischemia (HI) is a leading cause of death and disability in term newborns. Therapeutic hypothermia (HT) is the only recommended therapy. However, 30% still suffer from neurological deficits. Inflammation is a major hallmark of HI pathophysiology with myeloid cells being key players, participating either in progression or in resolution of injury-induced inflammation. In the present study, we investigated the impact of HT on the temporal and spatial dynamics of microglia/macrophage polarization after neonatal HI in newborn mice. Methods Nine-day-old C57BL/6 mice were exposed to HI through occlusion of the right common carotid artery followed by 1 h hypoxia. Immediately after HI, animals were cooled for 4 h or kept at physiological body core temperature. Analyses were performed at 1, 3 and 7 days post HI. Brain injury, neuronal cell loss, apoptosis and microglia activation were assessed by immunohistochemistry. A broad set of typical genes associated with classical (M1) and alternative (M2) myeloid cell activation was analyzed by real time PCR in ex vivo isolated CD11b+ microglia/macrophages. Purity and composition of isolated cells was determined by flow cytometry. Results Immediate HT significantly reduced HI-induced brain injury and neuronal loss 7 days post HI, whereas only mild non-significant protection from HI-induced apoptosis and neuronal loss were observed 1 and 3 days after HI. Microglia activation, i.e., Iba-1 immunoreactivity peaked 3 days after HI and was not modulated by HT. However, ex vivo isolated CD11b+ cells revealed a strong upregulation of the majority of M1 but also M2 marker genes at day 1, which was significantly reduced by HT and rapidly declined at day 3. HI induced a significant increase in the frequency of peripheral macrophages in sorted CD11b+ cells at day 1, which deteriorated until day 7 and was significantly decreased by HT. Conclusion Our data demonstrate that HT-induced neuroprotection is preceded by acute suppression of HI-induced upregulation of inflammatory genes in myeloid cells and decreased infiltration of peripheral macrophages, both representing potential important effector mechanisms of HT.

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“…Perinatal brain injury is a leading maternal-fetal health issue that is often associated with preterm birth, cerebral palsy (CP), neurodevelopmental delay, and a spectrum of negative health sequelae ( Burd et al, 2012 ; Duncan and Matthews, 2018 ; Hagberg et al, 2018 ). The mechanisms driving perinatal brain injury are varied, but are frequently tied to inflammation, infection, or hypoxia-ischemia, and subsequent cerebral white and gray matter cell death and damage ( Novak et al, 2018 ; Stolp et al, 2019 ; McClendon et al, 2019 ; Mülling et al, 2020 ). Hypoxic-ischemic contribution to brain injury is more clearly defined clinically in term vs. preterm infants ( Laptook, 2016 ; Gilles et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Fetal Neuroprotective Strategies: Therapeutic Agents and Their Underlying Synaptic Pathways

Elsayed

Boyer

Burd

2021

Front. Synaptic Neurosci.

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Synaptic signaling is integral for proper brain function. During fetal development, exposure to inflammation or mild hypoxic-ischemic insult may lead to synaptic changes and neurological damage that impairs future brain function. Preterm neonates are most susceptible to these deleterious outcomes. Evaluating clinically used and novel fetal neuroprotective measures is essential for expanding treatment options to mitigate the short and long-term consequences of fetal brain injury. Magnesium sulfate is a clinical fetal neuroprotective agent utilized in cases of imminent preterm birth. By blocking N-methyl-D-aspartate receptors, magnesium sulfate reduces glutamatergic signaling, which alters calcium influx, leading to a decrease in excitotoxicity. Emerging evidence suggests that melatonin and N-acetyl-L-cysteine (NAC) may also serve as novel putative fetal neuroprotective candidates. Melatonin has important anti-inflammatory and antioxidant properties and is a known mediator of synaptic plasticity and neuronal generation. While NAC acts as an antioxidant and a precursor to glutathione, it also modulates the glutamate system. Glutamate excitotoxicity and dysregulation can induce perinatal preterm brain injury through damage to maturing oligodendrocytes and neurons. The improved drug efficacy and delivery of the dendrimer-bound NAC conjugate provides an opportunity for enhanced pharmacological intervention. Here, we review recent literature on the synaptic pathways underlying these therapeutic strategies, discuss the current gaps in knowledge, and propose future directions for the field of fetal neuroprotective agents.

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

Cited by 27 publications

References 39 publications

DNase Treatment Prevents Cerebrospinal Fluid Block in Early Experimental Pneumococcal Meningitis

DNase Treatment Prevents Cerebrospinal Fluid Block in Early Experimental Pneumococcal Meningitis

Hypothermia modulates myeloid cell polarization in neonatal hypoxic–ischemic brain injury

Fetal Neuroprotective Strategies: Therapeutic Agents and Their Underlying Synaptic Pathways

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