Impact of K pneumoniae infection and/or exogenous surfactant protein-A2 (1A0) on alveolar macrophage miRNome in SP-A-knockout mice.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA723897 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14306200.fastq.gz | Fastqsanger.gz | |||
| SRR14306201.fastq.gz | Fastqsanger.gz | |||
| SRR14306202.fastq.gz | Fastqsanger.gz | |||
| SRR14306203.fastq.gz | Fastqsanger.gz | |||
| SRR14306204.fastq.gz | Fastqsanger.gz |
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Project description:Human SP-A1 and SP-A2, encoded by SFTPA1 and SFTPA2 and their genetic variants differentially impact alveolar macrophage (AM) functions and regulation, including the miRNome. single dose of SP-A exogenous treatment of SP-A-KO mice prior to infection, after infection, or at the time of infection significantly improved survival. we investigated the role of exogenous SP-A protein treatment on the regulation of AM miRNome in SP-A-KO mice at the time of infection. Towards this, SP-A-KO male and female mice were infected with K. pneumoniae alone or in combination with exogenous SP-A2 (1A0) protein for 6 h, and the expression levels of AM miRNAs, target mRNAs of the significant miRNAs, and pathways involved were studied. We found (i) significant differences in AM miRNome of KO in terms of sex and exposure; (ii) the expression of the overwhelming majority of miRNA targets in KO males were increased in response to infection and exogenous SP-A2 (1A0) protein treatment at the time of infection; (iii) miRNA-mRNA targets were involved in the pro-inflammatory response, anti-apoptosis, cell cycle, cellular growth and proliferation pathways. These data may assist in studying molecular mechanisms of exogenous SP-A mediated the AM miRNome regulation and potentially identify novel therapeutic targets for K. pneumoniae infection.
2023-04-21 | GSE173157 | GEO
Project description:BACKGROUND: Human SP-A1 and SP-A2, encoded by SFTPA1 and SFTPA2 and their genetic variants differentially impact alveolar macrophage (AM) functions and regulation, including the miRNome. We investigated whether miRNome differences previously observed between AM from SP-A2 and SP-A1/SP-A2 mice are due to continued qualitative differences or a delayed response of mice carrying a single gene. METHODS: Human transgenic (hTG) mice, carrying SP-A2 or both SP-A genes and SP-A-KO mice were exposed to filtered air (FA) or O3. AM miRNA levels, target gene expression and pathways determined 18 h after O3 exposure. RESULTS: We found: (a) Differences in miRNome due to sex, SP-A genotype, and exposure; (b) miRNome of both sexes was largely downregulated by O3 ; co-ex had fewer changed (≥2X) miRNAs than either group. (c) the number and direction of expression of genes with significant changes in males and females in co-ex is almost the opposite of those in SP-A2; (iv) The same pathways were found in the studied groups; (e) O3 exposure attenuated sex differences; a higher number of genotype-dependent and genotype-independent miRNAs was common in both sexes after O3 exposure. CONCLUSION: Qualitative differences between SP-A2 and co-ex persist 18 h post-O3, and O3 attenuates sex differences.
2021-01-06 | GSE158401 | GEO
Project description:In humans there are two surfactant protein A (SP-A) functional genes SFTPA1 and SFTPA2 encoding innate immune molecules, SP-A1 and SP-A2, respectively, with numerous genetic variants each. SP-A interacts and regulates many of the functions of alveolar macrophages (AM). It is shown that SP-A variants differ in their ability to regulate the AM miRNome in response to oxidative stress (OxS). Because humans have both SP-A gene products, we were interested to determine the combined effect of co-expressed SP-A1/SP-A2 (co-ex) in response to ozone (O3) induced OxS on AM miRNome. Human transgenic (hTG) mice, carrying both SP-A1/SP-A2 (6A2/1A0, co-ex) and SP-A- KO were utilized. The hTG and KO mice were exposed to filtered air (FA) or O3 and miRNA levels were measured after AM isolation with or without normalization to KO. We found: (i) The AM miRNome of co-ex males and females in response to OxS to be largely downregulated after normalization to KO, but after Bonferroni multiple comparison analysis only in females the AM miRNome remained significantly different compared to control (FA); (ii) The targets of the significantly changed miRNAs were downregulated in females and upregulated in males; (iii) Several of the validated mRNA targets were involved in pro-inflammatory response, anti-apoptosis, cell cycle, cellular growth and proliferation; (iv) The AM of SP-A2 male, shown, previously to have major effect on the male AM miRNome in response to OxS, shared similarities with the co-ex, namely in pathways involved in the pro-inflammatory response and anti-apoptosis but also exhibited differences with the cell-cycle, growth, and proliferation pathway being involved in co-ex and ROS homeostasis in SP-A2 male. We speculate that the presence of both gene products versus single gene products differentially impact the AM responses in males and females in response to OxS.
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Project description:Sash1 acts as a scaffold in TLR4 signaling. We generated Sash1-/- mice, which die in the perinatal period due to respiratory distress. Constitutive or endothelial-restricted Sash1 loss leads to a reduction of surfactant-associated protein synthesis. We show that Sash1 interacts with β-arrestin 1 downstream of the TLR4 pathway to activate Akt and eNOS in microvascular endothelial cells. Generation of nitric oxide downstream of Sash1 in endothelial cells activated cGMP in adjacent alveolar type 2 cells to induce transcription of surfactant genes. Thus we identify a critical cell nonautonomous function for Sash1 in embryonic development in which endothelial Sash1 affects alveolar type 2 cells and promotes pulmonary surfactant production through nitric oxide signaling. Lack of pulmonary surfactant is a major cause of respiratory distress and mortality in preterm infants, and these findings identify the endothelium as a potential target for therapy.
2019-05-01 | GSE123889 | GEO
Project description:The amount of pulmonary surfactant within type II cells and in the alveolar space, referred to as surfactant pool sizes, are tightly regulated. The molecular pathways that sense and regulate surfactant pool size within the alveolus have not been identified and constitute a fundamental knowledge gap in the field. Our data show that mice with a germline mutation in the orphan G-protein-coupled receptor, GPR116, have a 30-fold accumulation of surfactant phospholipids that causes respiratory distress in adult animals. This phenotype is associated with increased surfactant secretion and induction of the purinergic receptor P2RY2 in young animals, and lipid-laden macrophages and alveolar destruction in older animals. We further demonstrate that GPR116 mRNA expression is developmentally regulated in the murine lung with peak expression at birth when surfactant pool sizes are maximal. Within the lung, GPR116 protein expression is restricted to the apical plasma membrane of alveolar type I and type II epithelial cells. To better understand the roles and molecular mechanisms by which Gpr116 influences gene expression in lung, the effect of cell-selective deletion of Gpr116 (Gpr116D/D) on genome-wide mRNA expression profiles was determined in murine type II alveolar epithelial cells. Differentially expressed genes were identified from Affymetrix Murine GeneChips analysis and subjected to gene ontology classification promoter analysis, pathway mapping and literature mining.
2013-04-10 | E-GEOD-41417 | biostudies-arrayexpress
Project description:The amount of pulmonary surfactant within type II cells and in the alveolar space, referred to as surfactant pool sizes, are tightly regulated. The molecular pathways that sense and regulate surfactant pool size within the alveolus have not been identified and constitute a fundamental knowledge gap in the field. Our data show that mice with a germline mutation in the orphan G-protein-coupled receptor, GPR116, have a 30-fold accumulation of surfactant phospholipids that causes respiratory distress in adult animals. This phenotype is associated with increased surfactant secretion and induction of the purinergic receptor P2RY2 in young animals, and lipid-laden macrophages and alveolar destruction in older animals. We further demonstrate that GPR116 mRNA expression is developmentally regulated in the murine lung with peak expression at birth when surfactant pool sizes are maximal. Within the lung, GPR116 protein expression is restricted to the apical plasma membrane of alveolar type I and type II epithelial cells.
2013-04-10 | GSE41417 | GEO
Project description:Pulmonary alveolar proteinosis (PAP) results from a dysfunction of alveolar macrophages (AMs), chiefly due to disruptions in the signaling of granulocyte macrophage colony-stimulating factor (GM-CSF). We found that mice deficient for the B lymphoid transcription repressor BTB and CNC homology 2 (Bach2) developed PAP-like accumulation of surfactant proteins in the lungs. Bach2 was expressed in AMs, and Bach2-deficient AMs showed alterations in lipid handling in comparison with wild-type (WT) cells. Although Bach2-deficient AMs showed a normal expression of the genes involved in the GM-CSF signaling, they showed an altered expression of the genes involved in chemotaxis, lipid metabolism, and alternative M2 macrophage activation with increased expression of Ym1 and arginase-1, and the M2 regulator Irf4. Peritoneal Bach2-deficient macrophages showed increased Ym1 expression when stimulated with interleukin-4. More eosinophils were present in the lung and peritoneal cavity of Bach2-deficient mice compared with WT mice. The PAP-like lesions in Bach2-deficient mice were relieved by WT bone marrow transplantation even after their development, confirming the hematopoietic origin of the lesions. These results indicate that Bach2 is required for the functional maturation of AMs and pulmonary homeostasis, independently of the GM-CSF signaling. WT (n=8) and Bach2KO (n=3) AMs. One expreriment was performed.
2014-01-15 | E-GEOD-54050 | biostudies-arrayexpress
Project description:Differential sex-dependent regulation of the alveolar macrophage miRNome of SP-A2 and co-ex (SP-A1/SP-A2) and sex differences attenuation after 18h of ozone exposure
| PRJNA665153 | ENA
Project description:Surfactant protein A (SP-A) in addition to its surfactant-related functions interacts with alveolar macrophages (AM), the guardian cells of innate immunity, and regulates many of its functions under basal condition and in response to various insults, such as infection and oxidative stress. The human SP-A locus consists of two functional genes, SFTPA1 and SFTPA2, and one pseudogene. The functional genes encode human SP-A1 and SP-A2 proteins, respectively, and each has been shown to have several genetic variants. It has been shown that SP-A variants differ in their ability to regulate lung function mechanics and survival in response to bacterial infection. Here, we investigated the effect of hSP-A variants on the AM gene expression profile in response to K. pneumoniae (Kp) infection. We used four humanized transgenic (hTG) mice that each carried SP-A1 (6A2, 6A4) or SP-A2 (1A0, 1A3), and KO. The gene expression profiling of AM was performed after 6 h post-infection. We found: a) significant sex differences in the expression of AM genes between males and females; b) in response to infection, 858 (KO), 196 (6A2), 494 (6A4), 276 (1A0) and 397 (1A3) genes were identified (P < 0.05) and some of these were differentially expressed with ≥ 2 fold, specific to either males or females; c) significant gene-specific differences between the SP-A1 and SP-A2 variants; d) via Ingenuity Pathway Analysis (IPA) key pathways and molecules were identified that had direct interaction with TP53, TNF, and cell cycle signaling nodes; e) validation of key molecules exhibited significant differences in the expression between males and females; f) IPA for SP-A1 and SP-A2 variants and KO revealed, top diseases and bio-functions for males and females that contained a high number of genes involved in the inflammatory response, immunological disease, infectious diseases, respiratory diseases, cancer, and others. These results reveal for the first time a large number of biologically relevant functional pathways influenced by sex and SP-A variant in response to K. pneumoniae infection. These data may assist in studying molecular mechanisms of SP-A-mediated AM gene regulation and potentially identify novel therapeutic targets for K. pneumoniae infection.
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2021-12-07 | GSE186705 | GEO