Circ-Phkb promote LPS-induced acute lung injury via the TLR4/MyD88/NF-κB /CCL2 axis
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ABSTRACT:
PROVIDER: PRJNA938418 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23610245_1.fastq.gz | Fastqsanger.gz | |||
| SRR23610245_2.fastq.gz | Fastqsanger.gz | |||
| SRR23610246_1.fastq.gz | Fastqsanger.gz | |||
| SRR23610246_2.fastq.gz | Fastqsanger.gz |
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Project description:Our results showed that both circRNA and mRNA profiles are different from those of the sham group. A significant upregulation of circ-Phkb was observed in NR8383 cells and rats exposed to LPS. When circ-Phkb expression was reduced in NR8383 cells, apoptosis and inflammation were greatly reduced, and cell proliferation was increased, while overexpression of circ-Phkb have the opposite effect. In terms of mechanism, circ-Phkb suppression inhibits CCL2 expression via TLR4/MyD88/NF-κB pathway.
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Project description:Among the diseases caused by Toll-like receptor 4 (TLR4) abnormal activation by bacterial endotoxin, sepsis is the most dangerous one. The reprogramming of macrophages plays a crucial role in orchestrating the pathogenesis of sepsis. However, the precise mechanism underlying TLR4 activation in macrophages remained incompletely understood. Our studies revealed that upon lipopolysaccharide (LPS) stimulation, CREB-binding protein (CBP) was recruited to the TLR4 signalosome complex and resulted in pronounced acetylation in the TIR domains of TLR4, Myeloid differentiation factor 88 (MyD88) and MyD88 adapter-like (MAL), which significantly enhanced the activation of the NF-κB signaling pathway and polarization of M1 macrophages. In sepsis patients, significantly elevated TLR4-TIR acetylation was detected in CD16+ monocytes combined with elevated expression of M1 macrophage markers and production of pro-inflammatory cytokines. In contrast, histone deacetylase 1 (HDAC1) served as a key deacetylase in the deacetylation of the TIR domain complex. The inhibition of HDAC1 accelerated sepsis-associated syndromes, while the inhibition of CBP alleviated this process. Overall, our findings highlighted the crucial role of TIR domain complex acetylation in the regulation of inflammatory immune response and suggested that the reversible acetylation of the complex emerged as a promising therapeutic target for M1 macrophages during the progression of sepsis.
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Project description:BackgroundCircular RNAs (CircRNAs) have been associated with acute lung injury (ALI), but their molecular mechanisms remain unclear.MethodsThis study developed a rat model of lipopolysaccharide (LPS)-induced ALI and evaluated the modeling effect by hematoxylin and eosin staining, Masson's trichrome staining, lung wet-to-dry weight ratio, terminal deoxynucleotidyl transferase UTP nick end labeling (TUNEL), and enzyme-linked immunosorbent assay (ELISA) detection of inflammatory factors (interleukin-1β, tumor necrosis factor alpha, and interleukin-6). Using lung tissues from a rat model of LPS-induced ALI, we then conducted circRNA sequencing, mRNA sequencing, and bioinformatics analysis to obtain differential circRNA and mRNA expression profiles as well as potential ceRNA networks. Furthermore, we performed quantitative real-time polymerase chain reaction (qRT-PCR) assays to screen for circ-Phkb in ALI rat lung tissues, alveolar macrophages, and LPS-induced NR8383 cells. We conducted induction with or without LPS with circ-Phkb siRNA and overexpression lentivirus in NR8383. Cell Counting Kit-8, C5-Ethynyl-2'-deoxyuridine (Edu), TUNEL, and cytometry were used to identify proliferation and apoptosis, respectively. We detected inflammatory factors using ELISA. Finally, we used Western blot to detect the apoptosis-related proteins and TLR4/MyD88/NF-kB/CCL2 pathway activation.ResultsOur results revealed that both circRNA and mRNA profiles are different from those of the Sham group. We observed a significant circ-Phkb upregulation in NR8383 cells and LPS-exposed rats. Apoptosis and inflammation were greatly reduced when circ-Phkb expression was reduced in NR8383 cells, cell proliferation was increased, and circ-Phkb overexpression was decreased.ConclusionsIn terms of mechanism, circ-Phkb suppression inhibits CCL2 expression via the TLR4/MyD88/NF-kB pathway in LPS-induced alveolar macrophages.
| S-EPMC10826187 | biostudies-literature
Project description:The model was constructed to describe TLR4 induced NF-κB activation in native bone marrow-derived macrophages. It included processes of ligand (lipopolysaccharide) recognition, formation of dimer receptor complex and further signal transduction through TRAF6/TAK1 complex that leads to the activation of IKKα/β kinase, which in turn enables the NF-κB transcription factor phosphorylation and translocation in the cell nucleus, and induction of IkB and WIP1 (as an example of induced protein that promotes NF-κB dephosphorylation 2) gene transcription. Models were based on the current knowledge of TLR signaling framework, protein interactions within the TLR4 pathway, and up-to-date mathematical models describing Toll receptor activation.
The major important additions were made to TLR4 signaling description:
1) Receptor dimerization process
2) The existence of a basal nuclear NF-κB level (translocation)
3) NF-κB phosphorylation by IKK complex
2019-03-27 | MODEL1809230001 | BioModels