A microRNA-21–mediated SATB1/S100A9/NF-κB axis promotes chronic obstructive pulmonary disease pathogenesis

Kim, Richard; Sunkara, Krishna; Bracke, Ken; Jarnicki, Andrew G.; Donovan, Chantal; Hsu, Alan; Ieni, Antonio; Beckett, Emma L.; Galvão, Izabela; Wijnant, Sara; Ricciardolo, Fabio Luigi Massimo; Stefano, Antonino Di; Haw, Tatt Jhong; Liu, Gang; Ferguson, Angela; Palendira, Umamainthan; Wark, Peter; Conickx, Griet; Mestdagh, Pieter; Brusselle, Guy; Caramori, Gaetano; Foster, Paul S.; Horvat, Jay C.; Hansbro, Philip M.

doi:10.1126/scitranslmed.aav7223

Cited by 70 publications

(31 citation statements)

References 89 publications

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“…Patients with severe COVID-19 had higher serum levels of a set of miRNAs, including miR-21-5p and miR-22-3p, which were also upregulated in COVID-19 patients vs HCs, in agreement with literature data ( 18 ). MiR-21-5p has been implicated in different regulatory pathways and high circulating levels were associated with lung disease and cardiac fibrosis ( 48 , 49 ). Accordingly, in our COVID-19 cohort, miR-21-5p levels showed positive correlations with serum IL-6 and CPK, which are biomarkers of inflammation and myocardial damage, respectively.…”

Section: Discussionmentioning

confidence: 99%

Circulating microRNA signatures associated with disease severity and outcome in COVID-19 patients

et al. 2022

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BackgroundSARS-CoV-2 induces a spectrum of clinical conditions ranging from asymptomatic infection to life threatening severe disease. Host microRNAs have been involved in the cytokine storm driven by SARS-CoV-2 infection and proposed as candidate biomarkers for COVID-19.MethodsTo discover signatures of circulating miRNAs associated with COVID-19, disease severity and mortality, small RNA-sequencing was performed on serum samples collected from 89 COVID-19 patients (34 severe, 29 moderate, 26 mild) at hospital admission and from 45 healthy controls (HC). To search for possible sources of miRNAs, investigation of differentially expressed (DE) miRNAs in relevant human cell types in vitro.ResultsCOVID-19 patients showed upregulation of miRNAs associated with lung disease, vascular damage and inflammation and downregulation of miRNAs that inhibit pro-inflammatory cytokines and chemokines, angiogenesis, and stress response. Compared with mild/moderate disease, patients with severe COVID-19 had a miRNA signature indicating a profound impairment of innate and adaptive immune responses, inflammation, lung fibrosis and heart failure. A subset of the DE miRNAs predicted mortality. In particular, a combination of high serum miR-22-3p and miR-21-5p, which target antiviral response genes, and low miR-224-5p and miR-155-5p, targeting pro-inflammatory factors, discriminated severe from mild/moderate COVID-19 (AUROC 0.88, 95% CI 0.80-0.95, p<0.0001), while high leukocyte count and low levels of miR-1-3p, miR-23b-3p, miR-141-3p, miR-155-5p and miR-4433b-5p predicted mortality with high sensitivity and specificity (AUROC 0.95, 95% CI 0.89-1.00, p<0.0001). In vitro experiments showed that some of the DE miRNAs were modulated directly by SARS-CoV-2 infection in permissive lung epithelial cells.ConclusionsWe discovered circulating miRNAs associated with COVID-19 severity and mortality. The identified DE miRNAs provided clues on COVID-19 pathogenesis, highlighting signatures of impaired interferon and antiviral responses, inflammation, organ damage and cardiovascular failure as associated with severe disease and death.

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Section: Discussionmentioning

confidence: 99%

Circulating microRNA signatures associated with disease severity and outcome in COVID-19 patients

et al. 2022

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“…S100A9-ALDH1A1-RA signaling pathway that drives lethal brain relapse and could be targeted by pan-RAR antagonists to prevent cancer progression (Biswas et al, 2022). A microRNA-21-mediated SATB1/S100A9/NF-κB axis has been reported to promote chronic obstructive pulmonary disease pathogenesis (Kim et al, 2021). Of note, S100A9 was upregulated in TB patients, which suggested its damage-associated molecular-pattern features (Kuipers et al, 2013;Scott et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Association Between Plasma Exosomes S100A9/C4BPA and Latent Tuberculosis Infection Treatment: Proteomic Analysis Based on a Randomized Controlled Study

Xin

Cao

et al. 2022

Front. Microbiol.

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BackgroundIdentifying host plasma exosome proteins associated with host response to latent tuberculosis infection (LTBI) treatment might promote our understanding of tuberculosis (TB) pathogenesis and provide useful tools for implementing the precise intervention.MethodsBased on an open-label randomized controlled trial (RCT) aiming to evaluate the short-course regimens for LTBI treatment, plasma exosomes from pre- and post-LTBI treatment were retrospectively detected by label-free quantitative protein mass spectrometry and validated by a parallel reaction monitoring method for participants with changed or not changed infection testing results after LTBI treatment. Eligible participants for both screening and verification sets were randomly selected from the based-RCT in a 1:1 ratio by age and gender. Reversion was defined as a decrease in IFN-γ levels from >0.70 IU/ml prior to treatment to 0.20 IU/ml within 1 week of treatment. The predictive ability of the candidate proteins was evaluated by receiver operating characteristic (ROC) analysis.ResultsTotally, two sample sets for screening (n = 40) and validation (n = 60) were included. Each of them included an equal number of subjects with persistent positive or reversed QuantiFERON-TB Gold In-Tube (QFT) results after LTBI. A total of 2,321 exosome proteins were detected and 102 differentially expressed proteins were identified to be associated with QFT reversion. Proteins with high confidence and original values intact were selected to be further verified. Totally, 9 downregulated proteins met the criteria and were validated. After verification, C4BPA and S100A9 were confirmed to be still significantly downregulated (fold change <0.67, p < 0.05). The respective areas under the ROC curve were 0.73 (95% CI: 0.57–0.89) and 0.69 (95% CI: 0.52–0.86) for C4BPA and S100A9, with a combined value of 0.78 (95% CI: 0.63–0.93). The positive and negative predictive values for combined markers were 70.10% (95% CI: 50.22–86.30%) and 55.63% (95% CI: 29.17–61.00%).ConclusionOur findings suggest that downregulated C4BPA and S100A9 in plasma exosomes might be associated with a host positive response to LTBI treatment. Further studies are warranted to verify the findings and potential underlying mechanisms in varied populations with a larger sample size.

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“…Better understandings of the pathophysiology of disease development are recognized to be of increasing clinical importance, and identification of critical therapeutic targets specifically for COPD is of utmost importance [ 29 ]. RNA therapeutics provide high specificity and represent safer and reversible alternatives to DNA-based gene therapies, and RNA drugs potentially offer unique opportunities to expand the range of therapeutic targets with several of them have been approved or being currently in clinical trials [ 30 ]. This study uses RNA-seq to preliminarily explore the differentially expressed mRNAs, lncRNAs, miRNAs and circRNAs during the process of COPD, and tentatively reveal the interactions and potential functional mechanisms of these RNAs.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive identification of RNA transcripts and construction of RNA network in chronic obstructive pulmonary disease

et al. 2022

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Background Chronic obstructive pulmonary disease (COPD) is one of the world’s leading causes of death and a major chronic disease, highly prevalent in the aging population exposed to tobacco smoke and airborne pollutants, which calls for early and useful biomolecular predictors. Roles of noncoding RNAs in COPD have been proposed, however, not many studies have systematically investigated the crosstalk among various transcripts in this context. The construction of RNA functional networks such as lncRNA-mRNA, and circRNA-miRNA-mRNA interaction networks could therefore facilitate our understanding of RNA interactions in COPD. Here, we identified the expression of RNA transcripts in RNA sequencing from COPD patients, and the potential RNA networks were further constructed. Methods All fresh peripheral blood samples of three patients with COPD and three non-COPD patients were collected and examined for mRNA, miRNA, lncRNA, and circRNA expression followed by qRT-PCR validation. We also examined mRNA expression to enrich relevant biological pathways. lncRNA-mRNA coexpression network and circRNA-miRNA-mRNA network in COPD were constructed. Results In this study, we have comprehensively identified and analyzed the differentially expressed mRNAs, lncRNAs, miRNAs, and circRNAs in peripheral blood of COPD patients with high-throughput RNA sequencing. 282 mRNAs, 146 lncRNAs, 85 miRNAs, and 81 circRNAs were differentially expressed. GSEA analysis showed that these differentially expressed RNAs correlate with several critical biological processes such as “ncRNA metabolic process”, “ncRNA processing”, “ribosome biogenesis”, “rRNAs metabolic process”, “tRNA metabolic process” and “tRNA processing”, which might be participating in the progression of COPD. RT-qPCR with more clinical COPD samples was used for the validation of some differentially expressed RNAs, and the results were in high accordance with the RNA sequencing. Given the putative regulatory function of lncRNAs and circRNAs, we have constructed the co-expression network between lncRNA and mRNA. To demonstrate the potential interactions between circRNAs and miRNAs, we have also constructed a competing endogenous RNA (ceRNA) network of differential expression circRNA-miRNA-mRNA in COPD. Conclusions In this study, we have identified and analyzed the differentially expressed mRNAs, lncRNAs, miRNAs, and circRNAs, providing a systematic view of the differentially expressed RNA in the context of COPD. We have also constructed the lncRNA-mRNA co-expression network, and for the first time constructed the circRNA-miRNA-mRNA in COPD. This study reveals the RNA involvement and potential regulatory roles in COPD, and further uncovers the interactions among those RNAs, which will assist the pathological investigations of COPD and shed light on therapeutic targets exploration for COPD.

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A microRNA-21–mediated SATB1/S100A9/NF-κB axis promotes chronic obstructive pulmonary disease pathogenesis

Abstract: Inhibition of cigarette smoke–induced microRNA-21 suppresses chronic obstructive pulmonary disease through effects on a SATB1/S100A9/NF-κB axis.

Cited by 70 publications

References 89 publications

Circulating microRNA signatures associated with disease severity and outcome in COVID-19 patients

Circulating microRNA signatures associated with disease severity and outcome in COVID-19 patients

Association Between Plasma Exosomes S100A9/C4BPA and Latent Tuberculosis Infection Treatment: Proteomic Analysis Based on a Randomized Controlled Study

Comprehensive identification of RNA transcripts and construction of RNA network in chronic obstructive pulmonary disease

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