| 1. |
- Chumak, Tetyana, 1982, et al.
(författare)
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Maternal n-3 Polyunsaturated Fatty Acid Enriched Diet Commands Fatty Acid Composition in Postnatal Brain and Protects from Neonatal Arterial Focal Stroke
- 2022
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Ingår i: Translational Stroke Research. - : Springer Science and Business Media LLC. - 1868-4483 .- 1868-601X. ; 13:3, s. 449-461
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Tidskriftsartikel (refereegranskat)abstract
- The fetus is strongly dependent on nutrients from the mother, including polyunsaturated fatty acids (PUFA). In adult animals, n-3 PUFA ameliorates stroke-mediated brain injury, but the modulatory effects of different PUFA content in maternal diet on focal arterial stroke in neonates are unknown. This study explored effects of maternal n-3 or n-6 enriched PUFA diets on neonatal stroke outcomes. Pregnant mice were assigned three isocaloric diets until offspring reached postnatal day (P) 10-13: standard, long-chain n-3 PUFA (n-3) or n-6 PUFA (n-6) enriched. Fatty acid profiles in plasma and brain of mothers and pups were determined by gas chromatography-mass spectrometry and cytokines/chemokines by multiplex protein analysis. Transient middle cerebral artery occlusion (tMCAO) was induced in P9-10 pups and cytokine and chemokine accumulation, caspase-3 and calpain-dependent spectrin cleavage and brain infarct volume were analyzed. The n-3 diet uniquely altered brain lipid profile in naive pups. In contrast, cytokine and chemokine levels did not differ between n-3 and n-6 diet in naive pups. tMCAO triggered accumulation of inflammatory cytokines and caspase-3-dependent and -independent cell death in ischemic-reperfused regions in pups regardless of diet, but magnitude of neuroinflammation and caspase-3 activation were attenuated in pups on n-3 diet, leading to protection against neonatal stroke. In conclusion, maternal/postnatal n-3 enriched diet markedly rearranges neonatal brain lipid composition and modulates the response to ischemia. While standard diet is sufficient to maintain low levels of inflammatory cytokines and chemokines under physiological conditions, n-3 PUFA enriched diet, but not standard diet, attenuates increases of inflammatory cytokines and chemokines in ischemic-reperfused regions and protects from neonatal stroke.
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| 2. |
- Gravina, Giacomo, et al.
(författare)
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Proteomics identifies lipocalin-2 in neonatal inflammation associated with cerebrovascular alteration in mice and preterm infants
- 2023
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Ingår i: iScience. - 2589-0042. ; 26:7
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Tidskriftsartikel (refereegranskat)abstract
- Staphylococcus (S.) epidermidis is the most common nosocomial coagulase-negative staphylococci infection in preterm infants. Clinical signs of infection are often unspecific and novel markers to complement diagnosis are needed. We investigated proteomic alterations in mouse brain after S. epidermidis infection and in preterm infant blood. We identified lipocalin-2 (LCN2) as a crucial protein associated with cerebrovascular changes and astrocyte reactivity in mice. We further proved that LCN2 protein expression was associated with endothelial cells but not astrocyte reactivity. By combining network analysis and differential expression approaches, we identified LCN2 linked to blood C-reactive protein levels in pre term infants born <28 weeks of gestation. Blood LCN2 levels were associated with similar alterations of cytokines and chemokines in both infected mice and human preterm infants with increased levels of C-reactive protein. This experimental and clinical study suggests that LCN2 may be a marker of preterm infection/inflammation associated with cerebrovascular changes and neuroinflammation.
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| 3. |
- Ardalan, Maryam, 1979, et al.
(författare)
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Reelin cells and sex-dependent synaptopathology in autism following postnatal immune activation
- 2022
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 179:17, s. 4400-4422
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose: Autism spectrum disorders (ASD) are heterogeneous neurodevelopmental disorders with considerably increased risk in male infants born preterm and with neonatal infection. Here, we investigated the role of postnatal immune activation on hippocampal synaptopathology by targeting Reelin+ cells in mice with ASD-like behaviours. Experimental Approach: C57/Bl6 mouse pups of both sexes received lipopolysaccharide (LPS, 1mg·kg−1) on postnatal day (P) 5. At P45, animal behaviour was examined by marble burying and sociability test, followed by ex vivo brain MRI diffusion kurtosis imaging (DKI). Hippocampal synaptogenesis, number and morphology of Reelin+ cells, and mRNA expression of trans-synaptic genes, including neurexin-3, neuroligin-1, and cell-adhesion molecule nectin-1, were analysed at P12 and P45. Key Results: Social withdrawal and increased stereotypic activities in males were related to increased mean diffusivity on MRI-DKI and overgrowth in hippocampus together with retention of long-thin immature synapses on apical dendrites, decreased volume and number of Reelin+ cells as well as reduced expression of trans-synaptic and cell-adhesion molecules. Conclusion and Implications: The study provides new insights into sex-dependent mechanisms that may underlie ASD-like behaviour in males following postnatal immune activation. We identify GABAergic interneurons as core components of dysmaturation of excitatory synapses in the hippocampus following postnatal infection and provide cellular and molecular substrates for the MRI findings with translational value.
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| 4. |
- Ardalan, Maryam, 1979, et al.
(författare)
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Sex-Dependent Effects of Perinatal Inflammation on the Brain: Implication for Neuro-Psychiatric Disorders
- 2019
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 20:9
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Tidskriftsartikel (refereegranskat)abstract
- Individuals born preterm have higher rates of neurodevelopmental disorders such as schizophrenia, autistic spectrum, and attention deficit/hyperactivity disorders. These conditions are often sexually dimorphic and with different developmental trajectories. The etiology is likely multifactorial, however, infections both during pregnancy and in childhood have emerged as important risk factors. The association between sex- and age-dependent vulnerability to neuropsychiatric disorders has been suggested to relate to immune activation in the brain, including complex interactions between sex hormones, brain transcriptome, activation of glia cells, and cytokine production. Here, we will review sex-dependent effects on brain development, including glia cells, both under normal physiological conditions and following perinatal inflammation. Emphasis will be given to sex-dependent effects on brain regions which play a role in neuropsychiatric disorders and inflammatory reactions that may underlie early-life programming of neurobehavioral disturbances later in life.
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| 5. |
- Ardalan, Maryam, 1979, et al.
(författare)
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Sex-Dependent Gliovascular Interface Abnormality in the Hippocampus following Postnatal Immune Activation in Mice
- 2022
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Ingår i: Developmental neuroscience. - : S. Karger AG. - 0378-5866 .- 1421-9859. ; 44:4-5, s. 320-330
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Tidskriftsartikel (refereegranskat)abstract
- The neuro-gliovascular unit is a crucial structure for providing a balanced well-functioning environment for neurons and their synapses. Activation of the immune system during the developmental period is believed to affect the gliovascular unit, which may trigger neurodevelopmental and neurological/neuropsychiatric diseases. In this study, we hypothesized that vulnerability of the male brain to a neonatal insult was conditioned by sex-dependent differences in the impairment of the hippocampal gliovascular unit. Male and female C57BL/6J pups received lipopolysaccharide (LPS) (1 mg/kg) or saline on postnatal day (P) 5. Brains were collected at P12 and morphological quantifications of hippocampal fibrillary glial acid protein (GFAP(+)) astrocytes and ionized calcium-binding adaptor molecule 1 protein (Iba1+) microglia were performed by using 3-D image analysis together with measuring the length of CD31(+) and aquaporin-4 (AQP4(+)) vessels. We found a significant increase in the length of CD31(+) capillaries in the male LPS group compared to the saline group; however, coverage of capillaries by astrocytic end-feet (AQP4(+)) was significantly reduced. In contrast, there was a significant increase in AQP4(+) capillary length in female pups 1 week after LPS injection. GFAP(+) astrocytes via morphological changes in the hippocampus showed significant enhancement in the activity 1 week following LPS injection in male mice. We propose that neonatal inflammation could induce susceptibility to neurodevelopmental disorders through modification of hippocampal gliovascular interface in a sex-dependent manner.
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| 6. |
- Bay, V., et al.
(författare)
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Flinders sensitive line rats are resistant to infarction following transient occlusion of the middle cerebral artery
- 2020
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Ingår i: Brain Research. - : Elsevier BV. - 0006-8993. ; 1737
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Tidskriftsartikel (refereegranskat)abstract
- Background: Depression is a common complication of stroke and increases the risk of mortality and disability. Pre-stroke depression is a possible risk factor for stroke and has also been linked to adverse outcomes. The underlying mechanisms linking depression and stroke remain unclear. Preclinical models may provide novel insights, but models reflecting both conditions are lacking. Methods: In this study, we investigated the effects of a 45-min transient middle cerebral artery occlusion (MCAo) on infarct size in male adult Flinders Sensitive Line rats, a genetic animal model of depression, and their control strains Flinders Resistant Line and Sprague-Dawley rats. Infarct size was assessed by tetrazolium chloride (TTC) and microtubule-associated protein 2 (MAP2) staining after 48 h of reperfusion. Angiograms of the vascular structure of naive animals were produced with a mu-CT scanner. Results: Both Flinders strains had significantly smaller infarcts following MCAo compared to Sprague-Dawley rats. This effect does not appear to be due to changes in cerebrovascular architecture, as indicated by an initial exploration of vascular organization using angiograms, or body temperature regulation. Conclusions: Our study suggests that the rat strain does not influence infarct volumes following MCAo.
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| 7. |
- Chumak, Tetyana, 1982, et al.
(författare)
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Maternal n-3 enriched diet reprograms the offspring neurovascular transcriptome and blunts inflammation induced by endotoxin in the neonate
- 2024
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Ingår i: JOURNAL OF NEUROINFLAMMATION. - 1742-2094. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Infection during the perinatal period can adversely affect brain development, predispose infants to ischemic stroke and have lifelong consequences. We previously demonstrated that diet enriched in n-3 polyunsaturated fatty acids (n-3 PUFA) transforms brain lipid composition in the offspring and protects the neonatal brain from stroke, in part by blunting injurious immune responses. Critical to the interface between the brain and systemic circulation is the vasculature, endothelial cells in particular, that support brain homeostasis and provide a barrier to systemic infection. Here, we examined whether maternal PUFA-enriched diets exert reprograming of endothelial cell signalling in postnatal day 9 mice after modeling aspects of infection using LPS. Transcriptome analysis was performed on microvessels isolated from brains of pups from dams maintained on 3 different maternal diets from gestation day 1: standard, n-3 enriched or n-6 enriched diets. Depending on the diet, in endothelial cells LPS produced distinct regulation of pathways related to immune response, cell cycle, extracellular matrix, and angiogenesis. N-3 PUFA diet enabled higher immune reactivity in brain vasculature, while preventing imbalance of cell cycle regulation and extracellular matrix cascades that accompanied inflammatory response in standard diet. Cytokine analysis revealed a blunted LPS response in blood and brain of offspring from dams on n-3 enriched diet. Analysis of cerebral vasculature in offspring in vivo revealed no differences in vessel density. However, vessel complexity was decreased in response to LPS at 72 h in standard and n-6 diets. Thus, LPS modulates specific transcriptomic changes in brain vessels of offspring rather than major structural vessel characteristics during early life. N-3 PUFA-enriched maternal diet in part prevents an imbalance in homeostatic processes, alters inflammation and ultimately mitigates changes to the complexity of surface vessel networks that result from infection. Importantly, maternal diet may presage offspring neurovascular outcomes later in life.
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| 8. |
- Gravina, Giacomo, et al.
(författare)
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Transcriptome network analysis links perinatal Staphylococcus epidermidis infection to microglia reprogramming in the immature hippocampus
- 2023
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Ingår i: Glia. - 0894-1491. ; 71:9, s. 2234-2249
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Tidskriftsartikel (refereegranskat)abstract
- Staphylococcus epidermidis (S. epidermidis) is the most common nosocomial pathogen in preterm infants and associated with increased risk of cognitive delay, however, underlying mechanisms are unknown. We employed morphological, transcriptomic and physiological methods to extensively characterize microglia in the immature hippocampus following S. epidermidis infection. 3D morphological analysis revealed activation of microglia after S. epidermidis. Differential expression combined with network analysis identified NOD-receptor signaling and trans-endothelial leukocyte trafficking as major mechanisms in microglia. In support, active caspase-1 was increased in the hippocampus and using the LysM-eGFP knock-in transgenic mouse, we demonstrate infiltration of leukocytes to the brain together with disruption of the blood-brain barrier. Our findings identify activation of microglia inflammasome as a major mechanism underlying neuroinflammation following infection. The results demonstrate that neonatal S. epidermidis infection share analogies with S. aureus and neurological diseases, suggesting a previously unrecognized important role in neurodevelopmental disorders in preterm born children.
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| 9. |
- Kawamura, Takuya, et al.
(författare)
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Therapeutic Effect of Nicotinamide Mononucleotide for Hypoxic-Ischemic Brain Injury in Neonatal Mice
- 2023
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Ingår i: Asn Neuro. - 1759-0914. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- A clinical challenge remains in the treatment of hypoxic-ischemic brain injury in newborns. Nicotinamide adenine dinucleotide (NAD+) has beneficial effects in animal models of adult stroke. Here, we aimed to understand the short- and long-term neuroprotective effects of NAD+-promoting substance nicotinamide mononucleotide (NMN) in a well-established brain injury model in neonatal mice. Postnatal day (PND) 9 male and female mice were subjected to cerebral hypoxia-ischemia and treated with saline or NMN (50 mg/kg) immediately after hypoxia-ischemia. At different time points after hypoxia-ischemia, hippocampal NAD+, caspase-3 activity, protein expression of SIRT1, SIRT6, release of high mobility group box-1 (HMGB1), long-term neuropathological outcome, short-term developmental behavior, and long-term motor and memory function were evaluated. Neonatal hypoxia-ischemia reduced NAD+ and SIRT6 levels, but not SIRT1, in the injured hippocampus, while HMGB1 release was significantly increased. NMN treatment normalized hippocampal NAD+ and SIRT6 levels, while caspase-3 activity and HMGB1 release were significantly reduced. NMN alleviated tissue loss in the long-term and improved early developmental behavior, as well as motor and memory function. This study shows that NMN treatment provides neuroprotection in a clinically relevant neonatal animal model of hypoxia-ischemia in mice suggesting as a possible novel treatment for neonatal brain injury.Summary StatementNeonatal hypoxia-ischemia reduces nicotinamide adenine dinucleotide (NAD+) and SIRT6 levels in the injured hippocampus.Hippocampal high mobility group box-1 (HMGB1) release is significantly increased after neonatal hypoxia-ischemia.Nicotinamide mononucleotide (NMN) treatment normalizes hippocampal NAD+ and SIRT6 levels, with significant decrease in caspase-3 activity and HMGB1 release.NMN improves early developmental behavior, as well as motor and memory function. Graphical AbstractThis is a visual representation of the abstract.
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| 10. |
- Mottahedin, Amin, et al.
(författare)
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Effect of Neuroinflammation on Synaptic Organization and Function in the Developing Brain: Implications for Neurodevelopmental and Neurodegenerative Disorders
- 2017
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Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- The brain is a plastic organ where both the intrinsic CNS milieu and extrinsic cues play important roles in shaping and wiring neural connections. The perinatal period constitutes a critical time in central nervous system development with extensive refinement of neural connections, which are highly sensitive to fetal and neonatal compromise, such as inflammatory challenges. Emerging evidence suggests that inflammatory cells in the brain such as microglia and astrocytes are pivotal in regulating synaptic structure and function. In this article, we will review the role of glia cells in synaptic physiology and pathophysiology, including microglia-mediated elimination of synapses. We propose that activation of the immune system dynamically affects synaptic organization and function in the developing brain. We will discuss the role of neuroinflammation in altered synaptic plasticity following perinatal inflammatory challenges and potential implications for neurodevelopmental and neurodegenerative disorders.
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| 11. |
- Rayasam, A., et al.
(författare)
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Viral mimetic triggers cerebral arteriopathy in juvenile brain via neutrophil elastase and NETosis
- 2021
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016.
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Tidskriftsartikel (refereegranskat)abstract
- Stroke is among the top ten causes of death in children but has received disproportionally little attention. Cerebral arteriopathies account for up to 80% of childhood arterial ischemic stroke (CAIS) cases and are strongly predictive of CAIS recurrence and poorer outcomes. The underlying mechanisms of sensitization of neurovasculature by viral infection are undefined. In the first age-appropriate model for childhood arteriopathy-by administration of viral mimetic TLR3-agonist Polyinosinic:polycytidylic acid (Poly-IC) in juvenile mice-we identified a key role of the TLR3-neutrophil axis in disrupting the structural-functional integrity of the blood-brain barrier (BBB) and distorting the developing neurovascular architecture and vascular networks. First, using an array of in-vivo/post-vivo vascular imaging, genetic, enzymatic and pharmacological approaches, we report marked Poly-IC-mediated extravascular leakage of albumin (66kDa) and of a small molecule DiI (similar to 934Da) and disrupted tight junctions. Poly-IC also enhanced the neuroinflammatory milieu, promoted neutrophil recruitment, profoundly upregulated neutrophil elastase (NE), and induced neutrophil extracellular trap formation (NETosis). Finally, we show that functional BBB disturbances, NETosis and neuroinflammation are markedly attenuated by pharmacological inhibition of NE (Sivelestat). Altogether, these data reveal NE/NETosis as a novel therapeutic target for viral-induced cerebral arteriopathies in children.
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| 12. |
- Singh-Mallah, Gagandeep, et al.
(författare)
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N-Acetyl Cysteine Restores Sirtuin-6 and Decreases HMGB1 Release Following Lipopolysaccharide-Sensitized Hypoxic-Ischemic Brain Injury in Neonatal Mice
- 2021
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Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation and neonatal hypoxia-ischemia (HI) are important etiological factors of perinatal brain injury. However, underlying mechanisms remain unclear. Sirtuins are a family of nicotinamide adenine dinucleotide (NAD)+-dependent histone deacetylases. Sirtuin-6 is thought to regulate inflammatory and oxidative pathways, such as the extracellular release of the alarmin high mobility group box-1 (HMGB1). The expression and role of sirtuin-6 in neonatal brain injury are unknown. In a well-established model of neonatal brain injury, which encompasses inflammation (lipopolysaccharide, LPS) and hypoxia-ischemia (LPS+HI), we investigated the protein expression of sirtuin-6 and HMGB1, as well as thiol oxidation. Furthermore, we assessed the effect of the antioxidant N-acetyl cysteine (NAC) on sirtuin-6 expression, nuclear to cytoplasmic translocation, and release of HMGB1 in the brain and blood thiol oxidation after LPS+HI. We demonstrate reduced expression of sirtuin-6 and increased release of HMGB1 in injured hippocampus after LPS+HI. NAC treatment restored sirtuin-6 protein levels, which was associated with reduced extracellular HMGB1 release and reduced thiol oxidation in the blood. The study suggests that early reduction in sirtuin-6 is associated with HMGB1 release, which may contribute to neonatal brain injury, and that antioxidant treatment is beneficial for the alleviation of these injurious mechanisms.
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| 13. |
- Zelco, Aura, et al.
(författare)
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Type 2 Innate Lymphoid Cells Accumulate in the Brain After Hypoxia-Ischemia but Do Not Contribute to the Development of Preterm Brain Injury.
- 2020
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Ingår i: Frontiers in cellular neuroscience. - : Frontiers Media SA. - 1662-5102. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- The immune system of human and mouse neonates is relatively immature. However, innate lymphoid cells (ILCs), commonly divided into the subsets ILC1, ILC2, and ILC3, are already present in the placenta and other fetal compartments and exhibit higher activity than what is seen in adulthood. Recent reports have suggested the potential role of ILCs, especially ILC2s, in spontaneous preterm labor, which is associated with brain damage and subsequent long-term neurodevelopmental deficits. Therefore, we hypothesized that ILCs, and especially ILC2s, play a role in preterm brain injury.C57Bl/6J mice at postnatal day 6 were subjected to hypoxia-ischemia (HI) insult induced by left carotid artery ligation and subsequent exposure to 10% oxygen in nitrogen. The presence of ILCs and ILC2s in the brain was examined at different time points after HI. The contribution of ILC2s to HI-induced preterm brain damage was explored using a conditionally targeted ILC2-deficient mouse strain (Rorα fl/fl IL7r Cre ), and gray and white-matter injury were evaluated at 7 days post-HI. The inflammatory response in the injured brain was assessed using immunoassays and immunochemistry staining.Significant increases in ILCs and ILC2s were observed at 24 h, 3 days, and 7 days post-HI in the injured brain hemisphere compared with the uninjured hemisphere in wild-type mice. ILC2s in the brain were predominantly located in the meninges of the injured ipsilateral hemispheres after HI but not in the brain parenchyma. Overall, we did not observe changes in cytokine/chemokine levels in the brains of Rorα fl/fl IL7r Cre mice compared with wild type animals apart from IL-13. Gray and white-matter tissue loss in the brain was not affected after HI in Rorα fl/fl IL7r Cre mice. Correspondingly, we did not find any differences in reactive microglia and astrocyte numbers in the brain in Rorα fl/fl IL7r Cre mice compared with wild-type mice following HI insult.After HI, ILCs and ILC2s accumulate in the injured brain hemisphere. However, ILC2s do not contribute to the development of brain damage in this mouse model of preterm brain injury.
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