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Single-cell profiling of mouse spleen myeloid cells

ABSTRACT: Neonates are at higher risk of inflammatory disorders due to their immature immune system. The timely appearance of regulatory immune cells in early life contributes to the control of inflammation in neonates via induction of immunotolerance, the mechanisms underlying which remain poorly understood. In this study, we identified a subset of neonatal monocytes with high expression of transmembrane protein Neuropilin-1 (Nrp1), termed Nrp1high monocytes. Nrp1high monocytes displayed potent immunosuppressive activity and their frequencies declined in age-dependent manner. Deletion of Nrp1 in myeloid cells aggravated the severity of neonatal inflammatory disease necrotizing enterocolitis (NEC). Adoptive transfer of Nrp1high monocytes led to remission of NEC. Mechanistic studies showed that Nrp1, via binding with its ligand semaphorin-4a (Sema4a), induced intracellular p38-MAPK/mTOR signaling and activated transcription factor KLF4. KLF4 activation led to transcription of Nos2 and enhanced the production of nitric oxide, a key mediator of immunosuppression in monocytes. These observations uncover an important immunosuppressive axis in neonatal monocytes, and provides potential therapeutic strategy for inflammatory disorders in neonates.

ORGANISM(S): Mus musculus

PROVIDER: GSE254449 | GEO | 2024/04/17

REPOSITORIES: GEO

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Neuropilin-1 high monocytes protect against neonatal inflammation

Project description:Neonates are susceptible to inflammatory disorders such as necrotizing enterocolitis (NEC) due to their immature immune system. The timely appearance of regulatory immune cells in early life contributes to the control of inflammation in neonates, the underlying mechanisms of which remain poorly understood. In this study, we identified a subset of neonatal monocytes characterized with high levels of neuropilin-1 (Nrp1), termed Nrp1 high monocytes. Nrp1high monocytes displayed potent immunosuppressive activity as compared with their Nrp1low counterpart. Nrp1 deficiency in myeloid cells aggravated the severity of NEC, whereas adoptive transfer of Nrp1 highmonocytes led to remission of NEC. Mechanistic studies showed that Nrp1, via binding to its ligand Sema4a, induced intracellular p38-MAPK/mTOR signaling and activated the transcription factor KLF4. KLF4 transactivated Nos2 and enhanced the production of nitric oxide (NO), a key mediator of immunosuppression in monocytes. These observations uncover an important immunosuppressive axis in neonatal monocytes and provide a potential therapeutic strategy for inflammatory disorders in neonates.

2024-04-12 | GSE263510 | GEO

Maternal rhythm restricts neonatal inflammation via metabolic reprograming of myeloid cells

Project description:Disruption of circadian rhythm during pregnancy produced adverse health outcomes in offspring. However, the role of maternal circadian rhythms in infants’ immunity and their susceptibility to inflammation remains poorly understood. Here we reported that disruption of circadian rhythms in pregnant mice profoundly aggravated the severity of neonatal inflammatory disorders, including necrotizing enterocolitis (NEC) and sepsis. The diminished production of maternal-derived docosahexaenoic acid (DHA) and the impaired immunosuppressive function of myeloid-derived suppressor cells (MDSCs) in neonates played a dominant role in this process. Mechanistically, DHA enhanced the immunosuppressive function of neonatal MDSCs viaPPARγ mediated mitochondrial oxidative phosphorylation. Transfer of MDSCs or perinatal supplementation of DHA relieved neonatal inflammation induced by maternal rhythms disruption. These observations revealed an important role of maternal circadian rhythms in the control of neonatal inflammation via metabolic reprograming of myeloid cells.

2023-05-26 | GSE233545 | GEO

Maternal antibiotic exposure enhances neonatal ILC2 responses and aggravates allergic airway inflammation in adults [ATAC-seq]

2023-09-08 | GSE242246 | GEO

BCG vaccination reprograms the function of myeloid cells and aggravates necrotizing enterocolitis in neonates

Project description:Bacillus Calmette–Guérin (BCG) vaccination immediately after birth provides overall protection against immune disorders in healthy infants. However, for vulnerable infants such as preterm or low birth weights, delayed BCG vaccination is usually recommended. The mechanism underlying this clinical application remains obscure. Here we reported that BCG vaccination abrogated the transitory appearance of immunosuppressive myeloid cells in neonatal mice, that is myeloid-derived suppressor cells (MDSCs) represented as the important immunoprotection against inflammatory diseases in early life. A combination of single-cell transcriptome, metabolite profiling, and functional analysis revealed that the upregulation of mTOR/HIF1a signaling and the enhanced glycolysis explained the underlying mechanism. Consequently, BCG vaccination significantly exacerbated the severity of necrotizing enterocolitis (NEC), a common clinical emergency primarily affecting preterm or low birth weight infants. Adoptive transfer of MDSCs or pharmalogical inhibition of glycolysis or mTOR signaling efficiently relieved the severity of NEC upon BCG vaccination. These observations suggest that BCG may diminish the protective mechanism of myeloid cells and enhances the susceptibility of NEC in vulnerable neonates.

2023-06-12 | GSE234153 | GEO

IL-22 signaling attenuates necrotizing enterocolitis by promoting epithelial cell regeneration

Project description:Necrotizing enterocolitis (NEC) is a devastating intestinal inflammatory disorder that primarily affects premature infants. Despite decades of research, this disease remains a significant cause of death in the absence of efficient therapeutics. Interleukin (IL)-22 has been shown to play a critical role in maintaining the gut barrier, promoting epithelial regeneration, and controlling intestinal inflammation in adult animal models with an established microbiome. However, the importance of IL-22 signaling in the regulation of gut homeostasis and protection in neonates that lack an established microbiome remains unknown. Therefore, the aim of the current study is to investigate the role of IL-22 in the neonatal intestinal epithelium under homeostatic and inflammatory conditions by using a mouse model of NEC. Our data reveal that Il22 expression in neonatal murine intestine is negligible until weaning. In addition, both human and murine neonates lack IL-22 production during NEC. Mice deficient in IL-22 or mice lacking the expression of IL-22 receptor in intestinal epithelial cells, display a similar susceptibility of neonates to NEC consistent with the lack of endogenous IL-22 at this critical stage of intestinal development. Conversely, treatment with recombinant IL-22 during NEC substantially reduces disease severity. This IL-22-mediated protection is associated with enhanced epithelial regeneration and increased expression of several antimicrobial genes. Strikingly, despite an IL-22-mediated induction of an antimicrobial transcriptional program, the composition of the intestinal microbial communities remains unchanged. Taken together, this study demonstrates that an IL-22 signaling axis promotes protection against neonatal NEC through the induction of epithelial cell regeneration.

2021-05-18 | GSE155172 | GEO

Common inflammatory pathways between NEC and Crohn's disease

Project description:Necrotizing enterocolitis (NEC) is the most frequent life-threatening gastrointestinal disease experienced by premature infant occuring in neonatal intensive care units. NEC is associated with severe intestinal inflammation, intestinal perforation leading to mortality. The challenge for neonatologists is to detect early clinical manifestations of NEC. Therefore, one of the strategies to prevent or treat NEC would be to develop an early diagnostic tool allowing identification of preterm infants either at risk of developing NEC or at the onset of the disease. Illumina’s deep sequencing technology (RNA-seq) was used to establish the gene expression profile between resected ileal healthy preterm (control, n=5) and NEC diagnosed preterm infant (NEC, n=9) and analyzed by IPA Core analysis system. IPA analysis indicated that the most significant functional pathways overrepresented in NEC neonates were associated with innate immune functions, such as altered T and B cell signaling, B cell development, and the role of pattern recognition receptors in recognition of bacteria and viruses. Among genes that were strongly modulated in NEC neonates, we observed a high degree of similarity with those linked to the development of IBD. By comparing gene expression patterns between NEC and Crohn’s disease, we identified several new potential protein targets for helping to predict and/or diagnose NEC in preterm infant. Gene expression profile revealed an uncontrolled innate immune response in the intestine of NEC neonates. Moreover, comparative analysis between NEC and Crohn’s disease evidenced high degree of similarity between these two inflammatory diseases and allowed us to identify several new potential NEC biomarkers.

2016-01-25 | GSE64801 | GEO

Amniotic fluid and necrotizing enterocolitis in preterm pigs

2010-03-01 | GSE13515 | GEO

Amniotic fluid and necrotizing enterocolitis in preterm pigs

Project description:Preterm neonates are susceptible to gastrointestinal (GI) disorders such as necrotizing enterocolitis (NEC). Maternal milk, and especially colostrum, protects against NEC via growth promoting, immunomodulatory and antimicrobial factors. The fetal enteral diet, amniotic fluid (AF), contains similar bioactive components and we hypothesized that postnatal AF administration would reduce inflammatory responses and NEC in preterm neonates. Thirty preterm pigs (92% gestation) were delivered by caesarean section and fed total parental nutrition (TPN) for 48 h followed by enteral porcine colostrum (COLOS, n=7), infant formula (FORM, n=13) or formula + porcine AF (AF, n=10). Using a previously validated model of NEC in preterm pigs, we determined the structural, functional, microbiological and immunological responses to AF when administered prior to and after introduction of a suboptimal enteral formula diet. Keywords: Healthy versus inflammed tissues in relation to necrotizing enterocolitis Pigs from each treatment group (COLOS, n=4; FORM, n=6; and AF, n=7) were randomly selected for microarray analysis of frozen distal small intestine samples. The FORM group was further divided into formula-fed healthy pigs (F-HEA, n=3) and formula-fed NEC pigs (F-NEC, n=3) in order to compare sick versus healthy formula fed pigs. Equal amounts of total distal small intestinal RNA from all pigs were pooled to make the reference sample. Samples and reference pool were labelled with Oyster 550 and 650, respectively. The in-house spotted porcine oligonucleotide microarray version 4 (POM4) is a low density microarray consisting of 384 different oligonucleotide probes representing more than 200 different immune related genes.

2010-05-06 | E-GEOD-13515 | biostudies-arrayexpress

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Project description:We sought to determine the impact of chorioamnionitis exposure on the neonatal monocyte H3K4me3 histone modification landscape over the course of fetal and neonatal immune system development using ChIP-seq. H3K4me3 ChIP-seq was performed on umbilical cord blood purified CD14+ monocytes from healthy and chorioamnionitis-exposed extremely preterm neonates (under 30 weeks gestation), late preterm neonates (30-36 weeks gestation), and term neonates (37+ weeks gestation).

2018-08-01 | GSE111873 | GEO

Potentiation of regulatory T cell stability and function via a neuropilin-1:semaphorin-4a axis

Project description:Regulatory T cells (Treg) represent a critical immunoregulatory component of the immune system. The signals that maintain Treg stability and potentiate their function remain obscure. Here we show that the immune cell surface ligand semaphorin-4a (Sema4a) Sema treated and NRP1 knock outs were compared to untreated wild type T cell controls

2013-09-06 | E-GEOD-41185 | biostudies-arrayexpress

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