IBR1: A Novel Endogenous dsRNA Binding to the Helicase Domain of IFIH1 and Its Role in LPS-induced IFIH1 Activation and Macrophage M1 Polarization in ARDS
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ABSTRACT:
PROVIDER: PRJNA1036576 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26260900_1.fastq.gz | Fastqsanger.gz | |||
| SRR26260900_2.fastq.gz | Fastqsanger.gz | |||
| SRR26260901_1.fastq.gz | Fastqsanger.gz | |||
| SRR26260901_2.fastq.gz | Fastqsanger.gz | |||
| SRR26260902.fastq.gz | Fastqsanger.gz |
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Project description:Uncontrolled inflammatory responses driven by macrophages and monocytes play a crucial role in perpetuating lung injury and the severity of acute respiratory distress syndrome (ARDS). Previous studies have identified IFIH1 as a key regulator of macrophage M1 polarization in pneumonia-induced ARDS. IFIH1 is a cytosolic receptor responsible for recognizing viral double-stranded RNA (dsRNA) and activating inflammatory and antiviral signaling pathways. Interestingly, our observations indicate that IFIH1 can also be activated by lipopolysaccharide (LPS), a component of bacterial cell walls. However, the precise molecular mechanism underlying LPS-induced IFIH1 activation remains unclear. In our preliminary investigations, we have discovered a novel transcript, named IFIH1-binding RNA1 (IBR1), which is upregulated by LPS and gram-negative bacilli in monocytes and macrophages. We have confirmed that IBR1 interacts with the IFIH1 protein, forming a complex. Further experiments have revealed that IBR1, acting as an endogenous dsRNA, binds to the helicase domain of IFIH1 due to its local double-stranded structure. This specific interaction serves as the underlying molecular mechanism responsible for LPS-induced IFIH1 activation and subsequent macrophage M1 polarization in ARDS. Importantly, our observations indicate a significant upregulation of IBR1 expression in ARDS patients with gram-negative bacilli-induced pneumonia. Understanding the molecular mechanisms driving IFIH1 activation and macrophage M1 polarization in ARDS is of great importance for developing new therapeutic strategies to alleviate lung inflammation and improve patient outcomes. Further research is warranted to elucidate the precise roles of IBR1 and its potential as a therapeutic target in the management of ARDS.
2024-09-05 | GSE244502 | GEO
Project description:Uncontrolled inflammatory responses driven by macrophages and monocytes play a crucial role in perpetuating lung injury and the severity of acute respiratory distress syndrome (ARDS). Previous studies have identified IFIH1 as a key regulator of macrophage M1 polarization in pneumonia-induced ARDS. IFIH1 is a cytosolic receptor responsible for recognizing viral double-stranded RNA (dsRNA) and activating inflammatory and antiviral signaling pathways. Interestingly, our observations indicate that IFIH1 can also be activated by lipopolysaccharide (LPS), a component of bacterial cell walls. However, the precise molecular mechanism underlying LPS-induced IFIH1 activation remains unclear. In our preliminary investigations, we have discovered a novel transcript, named IFIH1-binding RNA1 (IBR1), which is upregulated by LPS and gram-negative bacilli in monocytes and macrophages. We have confirmed that IBR1 interacts with the IFIH1 protein, forming a complex. Further experiments have revealed that IBR1, acting as an endogenous dsRNA, binds to the helicase domain of IFIH1 due to its local double-stranded structure. This specific interaction serves as the underlying molecular mechanism responsible for LPS-induced IFIH1 activation and subsequent macrophage M1 polarization in ARDS. Importantly, our observations indicate a significant upregulation of IBR1 expression in ARDS patients with gram-negative bacilli-induced pneumonia. Understanding the molecular mechanisms driving IFIH1 activation and macrophage M1 polarization in ARDS is of great importance for developing new therapeutic strategies to alleviate lung inflammation and improve patient outcomes. Further research is warranted to elucidate the precise roles of IBR1 and its potential as a therapeutic target in the management of ARDS.
2024-09-05 | GSE247176 | GEO
Project description:IBR1: A Novel Endogenous dsRNA Binding to the Helicase Domain of IFIH1 and Its Role in LPS-induced IFIH1 Activation and Macrophage M1 Polarization in ARDS [RNA-seq]
| PRJNA1023280 | ENA
Project description:IBR1: A Novel Endogenous dsRNA Binding to the Helicase Domain of IFIH1 and Its Role in LPS-induced IFIH1 Activation and Macrophage M1 Polarization in ARDS [ATAC, ChIP]
| PRJNA1036578 | ENA
Project description:BackgroundUncontrolled inflammation caused by macrophages and monocytes plays a crucial role in worsening acute respiratory distress syndrome (ARDS). Previous studies have highlighted the importance of IFIH1 in regulating macrophage polarisation in ARDS triggered by pneumonia. However, the mechanisms by which IFIH1 is activated in ARDS remain unclear.MethodsIn this study, we utilised multiomics sequencing and molecular interaction experiments to explore the molecular mechanisms underlying IFIH1 activation in ARDS. Through the use of conditional gene knockout mice and primary cells, we demonstrated the significant role of these mechanisms in the development of ARDS. Additionally, we validated the associations between these mechanisms and ARDS by quantitative PCR analysis of CD14+ cells obtained from the peripheral blood of 140 ARDS patients.ResultsOur investigation revealed that lipopolysaccharide, a critical component derived from Gram-negative bacteria, activated IFIH1 by upregulating a novel transcript known as IFIH1-binding RNA1 (IBR1) in monocytes and macrophages. Specifically, as an endogenous double-stranded RNA, IBR1 bind to the helicase domain of IFIH1 because of its unique double-stranded structure. Deletion of IBR1 significantly reduced the activation of IFIH1, M1 polarisation of macrophages, and inflammatory lung injury in ARDS. Moreover, IBR1 directly induced M1 polarisation of macrophages and ARDS, whereas deletion of IFIH1 inhibited IBR1-induced macrophage M1 polarisation and inflammatory lung injury. Importantly, we observed a notable increase in IBR1 expression in ARDS patients with pneumonia caused by Gram-negative bacteria. Furthermore, we demonstrated that the delivery of IFIH1 mutants through exosomes effectively counteracted IBR1, thereby reducing pulmonary inflammation and alleviating lung injury.ConclusionsThis study revealed a novel mechanism involving IBR1, an endogenous double-stranded RNA (dsRNA) that binds to IFIH1, shedding light on the complex process of macrophage polarisation in ARDS. The administration of IFIH1 variants has the potential to eliminate pulmonary dsRNA and alleviate inflammatory lung injury in ARDS.HighlightsIn monocytes and macrophages, the endogenous double-stranded RNA, IFIH1-binding RNA 1 (IBR1), binds to the helicase domain of IFIH1 because of its unique double-stranded structure. IBR1 plays a significant role in macrophage polarisation and the development of acute respiratory distress syndrome (ARDS) induced by Gram-negative bacteria or lipopolysaccharide (LPS). Administration of IFIH1 variants has potential for eliminating pulmonary IBR1 and reducing inflammatory lung injury in ARDS patients.
| S-EPMC11420289 | biostudies-literature
Project description:Accumulated evidence has demonstrated that the macrophage phenotypic switch from M0 to M1 is crucial in the initiation of the inflammatory process of acute respiratory distress syndrome (ARDS). Better insight into the molecular control of M1 macrophages in ARDS may identify potential therapeutic targets. In the current study, 36 candidate genes associated with the severity of ARDS and simultaneously involved in M1-polarized macrophages were first screened through a weighted network algorithm on all gene expression profiles from the 26 ARDS patients and empirical Bayes analysis on the gene expression profiles of macrophages. STAT1, IFIH1, GBP1, IFIT3, and IRF1 were subsequently identified as hub genes according to connectivity degree analysis and multiple external validations. Among these candidate genes, IFIH1 had the strongest connection with ARDS through the RobustRankAggreg algorithm. It was selected as a crucial gene for further investigation. For in vitro validation, the RAW264.7 cell line and BMDMs were transfected with shIFIH1 lentivirus and plasmid expression vectors of IFIH1. Cellular experimental studies further confirmed that IFIH1 was a novel regulator for promoting M1 macrophage polarization. Moreover, gene set enrichment analysis (GSEA) and in vitro validations indicated that IFIH1 regulated M1 polarization by activating IRF3. In addition, previous studies demonstrated that activation of IFIH1-IRF3 was stimulated by viral RNAs or RNA mimics. Surprisingly, the current study found that LPS could also induce IFIH1-IRF3 activation via a MyD88-dependent mechanism. We also found that only IFIH1 expression without LPS or RNA mimic stimulation could not affect IRF3 activation and M1 macrophage polarization. These findings were validated on two types of macrophages, RAW264.7 cells and BMDMs, which expanded the knowledge on the inflammatory roles of IFIH1 and IRF3, suggesting IFIH1 as a potential target for ARDS treatment.
| S-EPMC7841399 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-09-05 | GSE247177 | GEO
Project description:Rat model of ARDS was induced by saline lavage and mechanical ventilation. miRNA from rat lungs were used for dual color DNA microarray hybridization with 3DNA 50 kit version 2. Two-condition experiment, CON vs. ARDS lung tissues. replicates: 6 control, 6 ARDS. One replicate per array.
2014-05-07 | E-GEOD-57223 | biostudies-arrayexpress
Project description:Rat model of ARDS was induced by saline lavage and mechanical ventilation. Total RNA from rat lungs were used for dual color DNA microarray hybridization with 3DNA 50 kit version 2. Two-condition experiment, CON vs. ARDS lung tissues. replicates: 5 control, 7 ARDS. One replicate per array.
2014-04-24 | E-GEOD-57011 | biostudies-arrayexpress
Project description:BackgroundA growing body of research has shown that the phenotypic change in macrophages from M0 to M1 is essential for the start of the inflammatory process in septic acute respiratory distress syndrome (ARDS). Potential treatment targets might be identified with more knowledge of the molecular regulation of M1 macrophages in septic ARDS.MethodsA multi-microarray interrelated analysis of high-throughput experiments from ARDS patients and macrophage polarization was conducted to identify the hub genes associated with macrophage M1 polarization and septic ARDS. Lipopolysaccharide (LPS) and Poly (I:C) were utilized to stimulate bone marrow-derived macrophages (BMDMs) for M1-polarized macrophage model construction. Knock down of the hub genes on BMDMs via shRNAs was used to screen the genes regulating macrophage M1 polarization in vitro. The cecal ligation and puncture (CLP) mouse model was constructed in knockout (KO) mice and wild-type (WT) mice to explore whether the screened genes regulate macrophage M1 polarization in septic ARDS in vivo. ChIP-seq and further experiments on BMDMs were performed to investigate the molecular mechanism.ResultsThe bioinformatics analysis of gene expression profiles from a clinical cohort of 26 ARDS patients and macrophage polarization found that the 5 hub genes (IFIH1, IRF1, STAT1, IFIT3, GBP1) may have a synergistic effect on macrophage M1 polarization in septic ARDS. Further in vivo investigations indicated that IFIH1, STAT1 and IRF1 contribute to macrophage M1 polarization. The histological evaluation and immunohistochemistry of the lungs from the IRF1-/- and WT mice indicated that knockout of IRF1 markedly alleviated CLP-induced lung injury and M1-polarized infiltration. Moreover, the molecular mechanism investigations indicated that knockdown of IFIH1 markedly promoted IRF1 translocation into the nucleus. Knockout of IRF1 significantly decreases the expression of STAT1. ChIP-seq and PCR further confirmed that IRF1, as a transcription factor of STAT1, binds to the promoter region of STAT1.ConclusionIRF1 was identified as the key molecule that regulates macrophage M1polarization and septic ARDS development in vivo and in vitro. Moreover, as the adaptor in response to infection mimics irritants, IFIH1 promotes IRF1 (transcription factor) translocation into the nucleus to initiate STAT1 transcription.
| S-EPMC9709523 | biostudies-literature