The Role of the E2F1 transcription factor in the innate immune response to systemic LPS
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ABSTRACT:
ORGANISM(S): synthetic construct Mus musculus
PROVIDER: GSE33902 | GEO | 2012/07/01
SECONDARY ACCESSION(S): PRJNA148261
REPOSITORIES: GEO
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Project description:Previous publications from our and other groups identified E2F1 as a transcription factor involved in the regulation of inflammatory response to Toll-like receptor ligands including LPS. In this study, we challenged E2F1-deficient mice with LPS systemically and demonstrated decreased survival despite attenuated inflammatory response compared with controls. Gene expression profiling of liver tissue identified a dampened transcriptional response in the coagulation cascade in B6;129(E2F1-/-) compared with B6x129 F2 mice. These data were further corroborated by increased prothrombin time, activated partial thromboplastin time, and fibrin split products in the blood of E2F1-deficient mice, suggesting disseminated intravascular coagulation as a consequence of uncontrolled sepsis providing at least a partial explanation for their decreased survival despite attenuated inflammatory response. To identify novel miRNAs involved in the innate immune response to LPS, we also performed miRNA profiling of liver tissue from B6;129(E2F1-/-) and B6x129 F2 mice treated with LPS systemically. Our analysis identified a set of miRNAs and their mRNA targets that are significantly differentially regulated in E2F1-deficient but not control mice including let-7g, miR-101b, miR-181b, and miR-455. These miRNAs represent novel regulators of the innate immune response. In summary, we used transcriptional and miRNA profiling to characterize the response of E2F1-deficient mice to systemic LPS.
| S-EPMC4587596 | biostudies-literature
Project description:Our recent study of gene expression in mice treated with LPS systemically identified the E2F1 transcription factor as a novel regulator of innate immune response in lung, liver, and spleen tissue. Our follow up studies showed that RNAi-mediated inhibition or E2F1 gene deficiency lead to reduced inflammatory response to LPS in vitro and in vivo. Furthermore, a clear role for the role of miRNAs in the regulation of innate immune response to LPS has emerged. In the current study, we further examined B6;129E2F1-/- and B6x126 F2 mice in the systemic LPS model and used gene expression profiling to identify a defect in the coagulation cascade that contributes to increased morbidity of B6;129E2F1-/- mice despite their reduced systemic inflammatory response. We also studied miRNA expression profiles identified miRNAs that are differentially expressed in B6;129E2F1-/- but not B6x129 F2 mice.
2012-07-01 | GSE33901 | GEO
Project description:Our recent study of gene expression in mice treated with LPS systemically identified the E2F1 transcription factor as a novel regulator of innate immune response in lung, liver, and spleen tissue. Our follow up studies showed that RNAi-mediated inhibition or E2F1 gene deficiency lead to reduced inflammatory response to LPS in vitro and in vivo. Furthermore, a clear role for the role of miRNAs in the regulation of innate immune response to LPS has emerged. In the current study, we further examined B6;129E2F1-/- and B6x126 F2 mice in the systemic LPS model and used gene expression profiling to identify a defect in the coagulation cascade that contributes to increased morbidity of B6;129E2F1-/- mice despite their reduced systemic inflammatory response. We also studied miRNA expression profiles identified miRNAs that are differentially expressed in B6;129E2F1-/- but not B6x129 F2 mice.
2012-07-01 | GSE33900 | GEO
Project description:Our recent study of gene expression in mice treated with LPS systemically identified the E2F1 transcription factor as a novel regulator of innate immune response in lung, liver, and spleen tissue. Our follow up studies showed that RNAi-mediated inhibition or E2F1 gene deficiency lead to reduced inflammatory response to LPS in vitro and in vivo. Furthermore, a clear role for the role of miRNAs in the regulation of innate immune response to LPS has emerged. In the current study, we further examined B6;129E2F1-/- and B6x126 F2 mice in the systemic LPS model and used gene expression profiling to identify a defect in the coagulation cascade that contributes to increased morbidity of B6;129E2F1-/- mice despite their reduced systemic inflammatory response. We also studied miRNA expression profiles identified miRNAs that are differentially expressed in B6;129E2F1-/- but not B6x129 F2 mice. 32 mice (4-6) per group, E2F+/+ or E2F-/- genotype, treated with saline or LPS, 6 or 20 hrs
2012-06-30 | E-GEOD-33901 | biostudies-arrayexpress
Project description:Our recent study of gene expression in mice treated with LPS systemically identified the E2F1 transcription factor as a novel regulator of innate immune response in lung, liver, and spleen tissue. Our follow up studies showed that RNAi-mediated inhibition or E2F1 gene deficiency lead to reduced inflammatory response to LPS in vitro and in vivo. Furthermore, a clear role for the role of miRNAs in the regulation of innate immune response to LPS has emerged. In the current study, we further examined B6;129E2F1-/- and B6x126 F2 mice in the systemic LPS model and used gene expression profiling to identify a defect in the coagulation cascade that contributes to increased morbidity of B6;129E2F1-/- mice despite their reduced systemic inflammatory response. We also studied miRNA expression profiles identified miRNAs that are differentially expressed in B6;129E2F1-/- but not B6x129 F2 mice. 32 mice (4-6) per group, E2F+/+ or E2F-/- genotype, treated with saline or LPS, 6 or 20 hrs
2012-06-30 | E-GEOD-33900 | biostudies-arrayexpress
Project description:Innate immunity is an ancient and conserved defense mechanism. Although host responses toward various pathogens have been delineated, how these responses are orchestrated in a whole animal is less understood. Through an unbiased genome-wide study performed in Caenorhabditis elegans, we identified a conserved function for endodermal GATA transcription factors in regulating local epithelial innate immune responses. Gene expression and functional RNAi-based analyses identified the tissue-specific GATA transcription factor ELT-2 as a major regulator of an early intestinal protective response to infection with the human bacterial pathogen Pseudomonas aeruginosa. In the adult worm, ELT-2 is required specifically for infection responses and survival on pathogen but makes no significant contribution to gene expression associated with intestinal maintenance or to resistance to cadmium, heat, and oxidative stress. We further demonstrate that this function is conserved, because the human endodermal transcription factor GATA6 has a protective function in lung epithelial cells exposed to P. aeruginosa. These findings expand the repertoire of innate immunity mechanisms and illuminate a yet-unknown function of endodermal GATA proteins.
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2017-03-07 | GSE95731 | GEO
Project description:Despite the introduction of vaccines, COVID-19 still affects millions of people worldwide. A better understanding of pathophysiology and the discovery of novel therapies are needed. One of the cells of interest in COVID-19 is the neutrophil. This cell type is being recruited to a site of inflammation as one of the first immune cells. In this project, we investigated a variety of neutrophils phenotypes during COVID-19 by measuring the expression of markers for migration, maturity, activation, gelatinase granules and secondary granules using flow cytometry. We show that neutrophils during COVID-19 exhibit altered phenotypes compared to healthy individuals. The activation level including NETs production and maturity of neutrophils seem to last longer during COVID-19 than expected for innate immunity. Neutrophils as one of the drivers of severe cases of COVID-19 are considered as potential treatment targets. However, for a successful implementation of treatment, there is a need for a better understanding of neutrophil functions and phenotypes in COVID-19. Our study answers some of those questions.
| S-EPMC9200737 | biostudies-literature
Project description:Fibroblast growth factor-23 (FGF-23) is a bone-derived hormone that activates FGFR/?-Klotho binary complexes in the kidney renal tubules to regulate phosphate reabsorption and vitamin D metabolism. The objective of this review is to discuss the emerging data that show that FGF-23 has functions beyond regulation of mineral metabolism, including roles in innate immune and hemodynamic responses. Excess FGF-23 is associated with inflammation and adverse infectious outcomes, as well as increased morbidity and mortality, particularly in patients with chronic kidney disease. Enhancer elements in the FGF-23 promoter have been identified that mediate the effects of inflammatory cytokines to stimulate FGF-23 gene transcription in bone. In addition, inflammation induces ectopic expression of FGF-23 and ?-Klotho in macrophages that do not normally express FGF-23 or its binary receptor complexes. These observations suggest that FGF-23 may play an important role in regulating innate immunity through multiple potential mechanisms. Circulating FGF-23 acts as a counter-regulatory hormone to suppress 1,25D production in the proximal tubule of the kidney. Since vitamin D deficiency may predispose infectious and cardiovascular diseases, FGF-23 effects on innate immune responses may be due to suppression of 1,25D production. Alternatively, systemic and locally produced FGF-23 may modulate immune functions through direct interactions with myeloid cells, including macrophages and polymorphonuclear leukocytes to impair immune cell functions. Short-acting small molecules that reversibly inhibit FGF-23 offer the potential to block pro-inflammatory and cardiotoxic effects of FGF-23 with less side effects compared with FGF-23 blocking antibodies that have the potential to cause hyperphosphatemia and soft tissue calcifications in animal models. In conclusion, there are several mechanisms by which FGF-23 impacts the innate immune system and further investigation is critical for the development of therapies to treat diseases associated with elevated FGF-23.
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Project description:Neurodegeneration is a hallmark of the human disease ataxia-telangiectasia (A-T) that is caused by mutation of the A-T mutated (ATM) gene. We have analyzed Drosophila melanogaster ATM mutants to determine the molecular mechanisms underlying neurodegeneration in A-T. Previously, we found that ATM mutants upregulate the expression of innate immune response (IIR) genes and undergo neurodegeneration in the central nervous system. Here, we present evidence that activation of the IIR is a cause of neurodegeneration in ATM mutants. Three lines of evidence indicate that ATM mutations cause neurodegeneration by activating the Nuclear Factor-?B (NF-?B) transcription factor Relish, a key regulator of the Immune deficiency (Imd) IIR signaling pathway. First, the level of upregulation of IIR genes, including Relish target genes, was directly correlated with the level of neurodegeneration in ATM mutants. Second, Relish mutations inhibited upregulation of IIR genes and neurodegeneration in ATM mutants. Third, overexpression of constitutively active Relish in glial cells activated the IIR and caused neurodegeneration. In contrast, we found that Imd and Dif mutations did not affect neurodegeneration in ATM mutants. Imd encodes an activator of Relish in the response to gram-negative bacteria, and Dif encodes an immune responsive NF-?B transcription factor in the Toll signaling pathway. These data indicate that the signal that causes neurodegeneration in ATM mutants activates a specific NF-?B protein and does so through an unknown activator. In summary, these findings suggest that neurodegeneration in human A-T is caused by activation of a specific NF-?B protein in glial cells.
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