Dataset Information

Long Non-Coding RNAs and the Innate Immune Response.

ABSTRACT: Innate immunity provides the initial defence against infection and it is now clear that long non-coding RNAs (lncRNAs) are important regulators of this response. Following activation of the innate response, we commonly see rapid induction of these lncRNAs and this is often mediated via the pro-inflammatory transcription factor, nuclear factor-?B (NF-?B). Knockdown studies have shown that lncRNAs tend to act in trans to regulate the expression of multiple inflammatory mediators and other responses. Mechanistically, many lncRNAs have demonstrated acting through heterogeneous nuclear ribonucleoproteins, complexes that are implicated chromatin re-modelling, transcription process and translation. In addition, these lncRNAs have also been shown to interact with multiple other proteins involved in the regulation of chromatin re-modelling, as well as those proteins involved in intracellular immune signalling, which include NF-?B. In this review, we will describe the evidence that supports this emerging role of lncRNA in the innate immune response.

SUBMITTER: Hadjicharalambous MR

PROVIDER: S-EPMC6630897 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Long Non-Coding RNAs and the Innate Immune Response.

Hadjicharalambous Marina R MR Lindsay Mark A MA

Non-coding RNA 20190419 2

Innate immunity provides the initial defence against infection and it is now clear that long non-coding RNAs (lncRNAs) are important regulators of this response. Following activation of the innate response, we commonly see rapid induction of these lncRNAs and this is often mediated via the pro-inflammatory transcription factor, nuclear factor-κB (NF-κB). Knockdown studies have shown that lncRNAs tend to act in trans to regulate the expression of multiple inflammatory mediators and other response ...[more]

PMID: 31010202

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Project description:Macrophages (Mφ) are immune cells that exhibit remarkable functional plasticity. Identification of novel endogenous factors that can regulate plasticity and innate immune functions of Mφ will unravel new strategies to curb immune-related diseases. Long non-coding RNAs (lncRNAs) are a class of endogenous, non-protein coding, regulatory RNAs that are increasingly being associated with various cellular functions and diseases. Despite their ubiquity and abundance, lncRNA-mediated epigenetic regulation of Mφ polarization and innate immune functions is poorly studied. This study elucidates the regulatory role of lncRNAs in monocyte to Mφ differentiation, M1/M2 dichotomy and innate immune responses. Expression profiling of eighty-eight lncRNAs in monocytes and in vitro differentiated M2 Mφ identified seventeen differentially expressed lncRNAs. Based on fold-change and significance, we selected four differentially expressed lncRNAs viz., RN7SK, GAS5, IPW, and ZFAS1 to evaluate their functional impact. LncRNA knockdown was performed on day 3 M2 Mφ and the impact on polarization was assessed on day 7 by surface marker analysis. Knockdown of RN7SK and GAS5 showed downregulation of M2 surface markers (CD163, CD206, or Dectin) and concomitant increase in M1 markers (MHC II or CD23). RN7SK or GAS5 knockdown showed no significant impact on CD163, CD206, or CD23 transcripts. M1/M2 markers were not impacted by IPW or ZFAS1 knockdown. Functional regulation of antigen uptake/processing and phagocytosis, two central innate immune pathways, by candidate lncRNA was assessed in M1/M2 Mφ. Compared to scramble, enhanced antigen uptake and processing were observed in both M1/M2 Mφ transfected with siRNA targeting GAS5 and RN7SK but not IPW and ZFAS1. In addition, knockdown of RN7SK significantly augmented uptake of labelled E. coli in vitro by M1/M2 Mφ, while no significant difference was in GAS5 silencing cells. Together, our results highlight the instrumental role of lncRNA (RN7SK and GAS5)-mediated epigenetic regulation of macrophage differentiation, polarization, and innate immune functions.

Project description:BackgroundPancreatic cancer is one of the most common malignant tumors with extremely poor prognosis. It is urgent to identify promising prognostic biomarkers for pancreatic cancer.MethodsA total of 266 patients with pancreatic adenocarcinoma (PAAD) in the Cancer Genome Atlas (TCGA)-PAAD cohort and the PACA-AU cohort were enrolled in this study. Firstly, prognostic tumor mutation burden (TMB)-related long non-coding RNAs (lncRNAs) were identified by DESeq2 and univariate analysis in the TCGA-PAAD cohort. And then, the TCGA-PAAD cohort was randomized into the training set and the testing set. Least absolute shrinkage and selection operator (LASSO) was used to construct the model in the training set. The testing set, the TCGA-PAAD cohort and the PACA-AU cohort was used as validation. The model was evaluated by multiple methods. Finally, functional analysis and immune status analysis were applied to explore the potential mechanism of our model.ResultsA prognostic model based on fourteen TMB-related lncRNAs was established in PAAD. Patients with High risk score was associated with worse prognosis compared to those with low risk score in all four datasets. Besides, the model had great performance in the prediction of 5-year overall survival in four datasets. Multivariate analysis also indicated that the risk score based on our model was independent prognostic factor in PAAD. Additionally, our model had the best predictive efficiency in PAAD compared to typical features and other three published models. And then, our findings also showed that high risk score was also associated with high TMB, microsatellite instability (MSI) and homologous recombination deficiency (HRD) score. Finally, we indicated that high risk score was related to low immune score and less infiltration of immune cells in PAAD.Conclusionwe established a 14 TMB-related lncRNAs prognostic model in PAAD and the model had excellent performance in the prediction of prognosis in PAAD. Our findings provided new strategy for risk stratification and new clues for precision treatment in PAAD.

Dataset Information

Long Non-Coding RNAs and the Innate Immune Response.

Publications

Long Non-Coding RNAs and the Innate Immune Response.

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