Genomeâ€Âwide postnatal changes in immunity following fetal inflammatory response
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001003635 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:The fetal inflammatory response (FIR) increases the risk of perinatal brain injury, particularly in extremely low gestational age newborns (ELGANs, < 28 weeks of gestation). One of the mechanisms contributing to such a risk is a postnatal intermittent or sustained systemic inflammation (ISSI) following FIR. The link between prenatal and postnatal systemic inflammation is supported by the presence of well-established inflammatory biomarkers in the umbilical cord and peripheral blood. However, the extent of molecular changes contributing to this association is unknown. Using RNA sequencing and mass spectrometry proteomics, we profiled the transcriptome and proteome of archived neonatal dried blood spot (DBS) specimens from 21 ELGANs. Comparing FIR-affected and unaffected ELGANs, we identified 782 gene and 27 protein expression changes of 50% magnitude or more, and an experiment-wide significance level below 5% false discovery rate. These expression changes confirm the robust postnatal activation of the innate immune system in FIR-affected ELGANs and reveal for the first time an impairment of their adaptive immunity. In turn, the altered pathway provide clues about the molecular mechanisms triggering ISSI after FIR, and the onset of perinatal brain injury.
2019-06-26 | PXD011626 | Pride
Project description:The study was aimed to identify mechanisms linked to complicated courses after severe trauma by a systems biology approach. In severe trauma, overwhelming systemic inflammation can result in adverse events and the development of complications, including sepsis. In a prospective study, RNA samples from circulating leukocytes from patients with multiple injury (injury severity score ⥠17) were analyzed for dynamic changes in gene expression over a period of 21 days by whole genome screening. Based on their clinical presentation, patients were divided into two subgroups: patients with secondary sepsis after trauma (n=5) and patients with systemic inflammation without infection (n=5). Expression cluster were defined by correlating gene expression data with clinical outcome parameters. Using unsupervised clustering, patients with systemic inflammation only and patients with sepsis showed a distinct expression pattern and the discrimination of clinical presentation was reflected by clustering of the samples. Explorative gene set analysis revealed robust upregulation of genes related to âhemoglobin metabolism/oxygen transportâ and âpathogenic E.coli infectionâ. 10 patients with multi-system trauma (ISS ⥠17 points) admitted to the Division of Trauma Surgery at the University Hospital Zurich were included. Whole blood from trauma patients was collected within the first 6 h after trauma (day 0) and on days 1, 2, 3, 5, 7, 10, 14, and 21. Total cellular RNA from circulating leukocytes was isolated using PaxGene Blood RNA Kit (PreAnalytix) for transcriptome profiling. RNA from blood of trauma patients was extracted and subjected to microarray analysis for comparison of longitudinal transcriptomic responses of patients. RNA samples of circulating leukocytes covering time points directly after admission (D0) and on the consecutive days (D1-D21) were subject to multifactorial microarray data analysis: Differences in dynamics of transcripts were assessed by contrasting time- and individual-resolved changes for sepsis and systemic inflammation without infection.
2015-11-01 | E-GEOD-70311 | biostudies-arrayexpress
Project description:Premature birth is frequently associated with abnormal brain development, leading to brain damage, the most common being diffuse white matter injury. Perinatal neuroinflammation, which relies primarily on microglial activation, contributes to the myelination failure by affecting oligodendrocytes. To better understand the pathophysiological mechanisms involved in encephalopathy of prematurity, we took advantage of a mouse model in which systemic injections of proinflammatory interleukin-1β (IL1B) disrupt oligodendrocyte differentiation, leading to hypomyelination and cognitive deficits. Newborn mice received intraperitoneal injections of IL1B from postnatal day (P) 1 to P5. At P5 and P10, brains were collected from six control (PBS) and six exposed (IL1B) mice; oligodendrocytes and microglial cells were sequentially isolated using antibodies coupled to magnetic beads targeting O4 and CD11b, respectively. Gene expression analysis performed on Agilent microarray revealed that perinatal inflammation induced major changes in gene expression in both cell types. By improving our understanding of the cellular mechanisms involved in encephalopathy of prematurity, this study could ultimately help design neuroprotective strategies.
2022-12-14 | GSE197563 | GEO
Project description:Keratin 1 (KRT1) and its heterodimer partner keratin 10 (KRT10) constitute the intermediate filament cytoskeleton of suprabasal skin keratinocytes. They participate in formation of the epidermal barrier, which protects against dehydration and inflammation. Mutations in KRT1 cause keratinopathic ichthyosis with erythema, recurrent inflammation, and barrier defects. Here, we show that genetic deletion of Krt1 in mice causes a defective inside-out epidermal barrier, pre- and postnatal increases in Mrp8/Mrp14, interleukin (IL) 18, IL-33, and thymic stromal lymphopoietin (TSLP) in skin extracts, and systemic release of IL-18 into newborn serum. Perinatal lethality was partially rescued by treatment with glucocorticoids to promote barrier repair or with IL- 18-blocking antibodies in utero. In human keratinocytes, IL-18 release was cellautonomous and caspase-1-dependent, indicating KRT1-dependent inflammasome activation. Our data reveal a novl function of KRT1 in controlling inflammasome activity and stimulating barrier formation, thereby integrating the keratin cytoskeleton into the epidermal immune response. In view of their widespread expression, keratins merit investigation of their functions in inflammatory conditions, including asthma and inflammatory bowel disorders. Total RNA was obtained from epidermis or full-thickness skin of Krt1+/+ and Krt1-/- mice (C57BL/6 background) at P0 (newborn).
2012-12-01 | E-GEOD-32951 | biostudies-arrayexpress
Project description:Perinatal brain injury is a major clinical problem associated with high neonatal mortality and morbidity and an increased risk of life-long chronic disabilities. Despite improved survival rates, the absolute numbers of neurological handicaps of perinatal origin have not decreased. There is currently no pharmacological treatment providing neuroprotction in neonates. As activation of the innate immune response is a key contributing factor to brain injury in both term and preterm infants we investigated the therapeutic potential of novel immunomodulatory innate defence regulator peptides (IDRs) in perinatal brain injury. IDR-1018 significantly reduced the production of inflammatory mediators by LPS-stimulated microglia cells in vitro. IDR-1018 was also neuroprotective in a clinically-relevant animal model of neonatal brain injury, exerting effects on regulatory molecules of TLR-, Ca2+- and p53-signaling. Of utmost importance, IDR-1018 markedly protected both white and grey brain matter when administered after the injury, thus has tremendous applicability to the clinical setting. Here we demonstrate for the first time that peripheral administration of an immunomodulatory peptide is neuroprotective in vivo in a clinically relevant model of perinatal brain damage.
2016-09-17 | GSE36215 | GEO
Project description:Perinatal brain injury is a major clinical problem associated with high neonatal mortality and morbidity and an increased risk of life-long chronic disabilities. Despite improved survival rates, the absolute numbers of neurological handicaps of perinatal origin have not decreased. There is currently no pharmacological treatment providing neuroprotction in neonates. As activation of the innate immune response is a key contributing factor to brain injury in both term and preterm infants we investigated the therapeutic potential of novel immunomodulatory innate defence regulator peptides (IDRs) in perinatal brain injury. IDR-1018 significantly reduced the production of inflammatory mediators by LPS-stimulated microglia cells in vitro. IDR-1018 was also neuroprotective in a clinically-relevant animal model of neonatal brain injury, exerting effects on regulatory molecules of TLR-, Ca2+- and p53-signaling. Of utmost importance, IDR-1018 markedly protected both white and grey brain matter when administered after the injury, thus has tremendous applicability to the clinical setting. Here we demonstrate for the first time that peripheral administration of an immunomodulatory peptide is neuroprotective in vivo in a clinically relevant model of perinatal brain damage. In this second data set, adult mice were used for comparison.
2016-09-17 | GSE51026 | GEO
Project description:During the perinatal period, unique metabolic adaptations support energetic requirements for rapid growth. To gain insight into perinatal adaptations, quantitative proteomics were performed comparing the livers of yorkshire pigs at postnatal day seven and adult. These data revealed differences in the metabolic control of liver function including significant changes in lipid and carbohydrate metabolic pathways. Newborn livers showed an enrichment of proteins in lipid catabolism and gluconeogenesis concomitant with elevated liver carnitine and acylcarnitines levels. Sugar kinases were some of the most dramatically differentially enriched proteins comparing neonatal and adult pigs including galactokinase 1 (Galk1), ketohexokinase (KHK), hexokinase 1 (HK1) and hexokinase 4 (GCK). Interestingly, hexokinase domain containing 1 (HKDC1), an enigmatic fifth hexokinase associated with glucose disturbances in pregnant women was highly enriched in the liver during the prenatal and perinatal periods and continuously declined throughout postnatal development in pigs and mice. These changes were confirmed via Western blot and mRNA expression. These data provide new insights into the developmental and metabolic adaptations in the liver during the transition from the perinatal period to adulthood in multiple mammalian species.
2023-07-17 | PXD037264 | Pride
Project description:Keratin 1 (KRT1) and its heterodimer partner keratin 10 (KRT10) constitute the intermediate filament cytoskeleton of suprabasal skin keratinocytes. They participate in formation of the epidermal barrier, which protects against dehydration and inflammation. Mutations in KRT1 cause keratinopathic ichthyosis with erythema, recurrent inflammation, and barrier defects. Here, we show that genetic deletion of Krt1 in mice causes a defective inside-out epidermal barrier, pre- and postnatal increases in Mrp8/Mrp14, interleukin (IL) 18, IL-33, and thymic stromal lymphopoietin (TSLP) in skin extracts, and systemic release of IL-18 into newborn serum. Perinatal lethality was partially rescued by treatment with glucocorticoids to promote barrier repair or with IL- 18-blocking antibodies in utero. In human keratinocytes, IL-18 release was cellautonomous and caspase-1-dependent, indicating KRT1-dependent inflammasome activation. Our data reveal a novl function of KRT1 in controlling inflammasome activity and stimulating barrier formation, thereby integrating the keratin cytoskeleton into the epidermal immune response. In view of their widespread expression, keratins merit investigation of their functions in inflammatory conditions, including asthma and inflammatory bowel disorders.
2012-12-01 | GSE32951 | GEO
Project description:Following spinal cord injury, skeletal muscle loss is rapid. This severe atrophy is attributed to declines in protein synthesis and increases in protein breakdown. However, the signaling mechanisms controlling these changes are not well understood. Nine male patients and one female patient with spinal cord injury (SCI) (Mean ± SEM = 43.9 ± 6.7 yrs) were recruited for this study. Six patients were quadriplegics and four patients were paraplegics. Inclusion criteria were as follows: patients above the age of 18 yrs, absence of severe brain injury (Glasgow Coma Scale > 13), absence of muscle-crush injury or compartment syndrome, absence of all of the following conditions: hypoxic injury, systemic sepsis, systemic inflammatory or autoimmune disease, and malignancy. Muscle biopsies were obtained from the vastus lateralis muscles of the SCI patients two days and five days post-SCI. Biopsies collected two days post-SCI were included in the current analysis. Expression changes were measured by microarray and gene clustering; identification of enriched functions and canonical pathways were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) and Ingenuity Pathway Analysis (IPA). Functional analysis found that 48h following SCI expression, gene expression changes were related to decreases in metabolic functions such as the tricarboxylic acid cycle and oxidative phosphorylation as well as increases in functions associated with protein degradation such as proteasome activity and ubiquitination. Furthermore, increases in expression of metallothioneins were found to be the most over-represented functional group in the DAVID analysis. Results from this study showed that functional categories of gene expression changes in human skeletal muscle are consistent with previous findings in animals. Muscle biopsies were obtained from the vastus lateralis muscles of the SCI patients two days and five days post-SCI. (N = 10). A 5mm Berstrom biopsy needle was used. Biopsy samples were immediately snap-frozen in liquid nitrogen upon excision. All samples were stored at -80° C until analysis.
2010-10-23 | E-GEOD-21497 | biostudies-arrayexpress
Project description:Hepcidin is demonstrated to be the key iron regulatory hormone, produced by the liver. Here we show an unexpected role of hepcidin as a master initiator of the local and systemic inflammatory response. We found that hepcidin was highly expressed in the colon of two major idiopathic inflammatory bowel diseases : Crohn's disease (CD) and ulcerative colitis (UC). Thanks to the generation of intestinal specific hepcidin KO mice (Hepc{delta}int), we found in a DSS-induced colitis model that hepcidin mediated the induction of key inflammatory cytokines and was protective against intestinal injury. In a model of LPS-induced acute inflammation, intestinal hepcidin expression was increased through a TLR4 dependent pathway andwas required for intestinal neutrophil infiltration and inflammation. Strikingly, intestinal hepcidin was absolutely required for the systemic production of key inflammatory cytokines (IL-6, CXCL1, TNF-alpha ...) as well as for the setting of the hypoferremia of inflammation. In a sepsis model, Hepc{delta}int mice were protected against LPS-induced mortality. Mechanistically, we showed that hepcidin was a direct neutrophil chemoattractant and a proinflammatory molecule in macrophages through a Myd88 dependent pathway. Altogether, we demonstrated that Hepcidin is a key new essential component of the immune system and may be a promising target in many inflammatory diseases. We used microarrays to detail the global program of gene expression of BMDM treat with hepcidin for 1 hour.
2016-07-16 | E-GEOD-71073 | biostudies-arrayexpress