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Brucella Omp25 Upregulates miR-155, miR-21-5p, and miR-23b to Inhibit Interleukin-12 Production via Modulation of Programmed Death-1 Signaling in Human Monocyte/Macrophages.

ABSTRACT: Brucella spp. infection results in compromised Type1 (Th1) cellular immune response. Several reports have described an immunomodulatory function for Brucella major outer membrane protein Omp25. However, the mechanism by which Omp25 modulates macrophage dysfunction has not been defined. Herein, we reported that Omp25-deficient mutant of Brucella suis exhibited an enhanced ability to induce interleukin (IL)-12 whereas ectopic expression of Omp25 protein inhibited TLR agonists-induced IL-12 p70 production through suppression of both IL-12 p40 and p35 subunit expression in THP-1 cells. In addition, Omp25 significantly upregulated miR-155, -23b and -21-5p, as well as the immunomodulator molecule programmed death-1 (PD-1) in monocyte/macrophages. The upregulation of miR-155 and -23b correlated temporally with decreased TAB2 levels, I?B phosphorylation and IL-12 p40 levels by targeting TAB2 and il12B 3' untranslated region (UTR), respectively, while miR-21-5p increase directly led to the reduction of lipopolysaccharide (LPS)/R848-induced IL-12 p35 protein by targeting il12A 3'UTR. Consistent with this finding, reduction of miR-155 and -23b attenuated the inhibitory effects of Omp25 on LPS/R848-induced IL-12 p40 expression at both transcriptional and posttranscriptional levels, while reduction of miR-21-5p attenuated the inhibitory effects of Omp25 on LPS/R848-induced IL-12 p35 expression at the posttranscriptional level, together significantly enhanced IL-12 p70 production upon LPS/R848 stimulation. We also found that blocking PD-1 signaling decreased the expression of miR-155, -23b and -21-5p induced by Omp25 and enhanced IL-12 production in monocyte/macrophages. Altogether, these data demonstrate that Brucella Omp25 induces miR-155, -23b and -21-5p to negatively regulate IL-12 production at both transcriptional and posttranscriptional levels via regulation of PD-1 signaling, which provides an entirely new mechanism underlying monocyte/macrophages dysfunction during Brucella spp. infection.

SUBMITTER: Cui B

PROVIDER: S-EPMC5483987 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Brucella Omp25 Upregulates miR-155, miR-21-5p, and miR-23b to Inhibit Interleukin-12 Production via Modulation of Programmed Death-1 Signaling in Human Monocyte/Macrophages.

Cui Beibei B Liu Wenli W Wang Xiaoya X Chen Yu Y Du Qian Q Zhao Xiaomin X Zhang Hai H Liu Shan-Lu SL Tong Dewen D Huang Yong Y

Frontiers in immunology 20170626

Brucella spp. infection results in compromised Type1 (Th1) cellular immune response. Several reports have described an immunomodulatory function for Brucella major outer membrane protein Omp25. However, the mechanism by which Omp25 modulates macrophage dysfunction has not been defined. Herein, we reported that Omp25-deficient mutant of Brucella suis exhibited an enhanced ability to induce interleukin (IL)-12 whereas ectopic expression of Omp25 protein inhibited TLR agonists- ...[more]

PMID: 28694807

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Project description:Introduction: Acute graft vs. host disease (aGvHD) is a frequent complication following allogeneic haematopoeitic transplantation (HSCT). Despite recent advances, there are no universally accepted biomarkers to determine development of aGvHD. MicroRNAs miR-146a and miR-155 have been previously associated with aGvHD and show promise as clinically translatable biomarkers. In this study, we performed comprehensive expression profiling of miR-146a, miR-155, and miR-155* expression in aGvHD target tissue and biofluids and relate expression to post-HSCT outcomes. Materials and Methods: MicroRNA expression was assessed by qRT-PCR in gastrointestinal (n = 31) and skin (n = 31) biopsies as well as serum (exploratory cohort n = 34, verification cohort n = 81, diagnostic cohort n = 65) and urine (exploratory cohort n = 30, verification cohort n = 56, diagnostic cohort n = 20) biofluids, including extracellular vesicle (EV) cohorts (serum EV n = 15, urine EV n = 30). Expression was related to aGvHD incidence, severity and overall survival. Results: In GI samples, expression of miR-155 (p = 0.03) and miR-146a (p = 0.03) was higher at aGvHD onset compared to patients with no GvHD. In skin biopsies, expression of miR-155 (p = 0.004) was upregulated in aGvHD patients compared to normal control skin. Expression of miR-146a was higher in aGvHD compared to no aGvHD biopsies (p = 0.002). In serum, miR-155 (p = 0.03) and miR-146a (p = 0.02) expression was higher at day 14 (D14), while in urine expression was elevated at D7 post-HSCT in patients who developed aGvHD compared to those disease-free. This was verified in an independent serum (miR-155 p = 0.005, miR-146a p = 0.003) and urine (miR-155 p = 0.02, miR-146a p = 0.04) cohort, where both microRNAs were also associated with aGvHD by ROC analysis. In serum and urine samples taken at the time of aGvHD symptoms, expression of miR-155 and miR-146a was also elevated (serum miR-155 p = 0.03, miR-146a p < 0.001; urine miR-155 p = 0.02, miR-146a p = 0.02). In contrast, miR-146a and miR-155 were downregulated at D14 in serum EVs and at D7 in urine EVs in patients who developed aGvHD compared to those that remained disease-free, in both an exploratory (serum miR-155 p = 0.02, miR-146a p = 0.06; urine miR-155 p = 0.02, miR-146a p = 0.07) and an independent cohort (serum miR-155 p = 0.01, miR-146a p = 0.02). Conclusions: These results further support a role for miR-155 and miR-146a as non-invasive, clinically relevant biomarkers for aGvHD. However, the link between their involvement in generalized inflammation and in specific pathophysiology requires further investigation at a systemic level.

Project description:BackgroundThe differentiation of stem cells from exfoliated deciduous teeth (SHEDs) into odontoblasts determines the regeneration of dentin-pulp complex. Non-coding RNAs (ncRNAs), including microRNA (miRNA) and long non-coding RNA (lncRNA), participate in many multiple biological processes, but the specific miRNAs involved in odontogenesis are incompletely defined. It was confirmed that lncRNA IGFBP7-AS1 could positively regulate odontogenetic differentiation in SHEDs. To investigate the downstream mechanisms of this process, miR-335-3p and miR-155-5p were found to be closely related with SHED odontogenic differentiation through whole-genome sequencing. The aim of the current study was to determine the role of miR-335-3p/miR-155-5p in IGFBP7-AS1-enhanced SHED differentiation and explore the potential mechanism of IGFBP7-AS1-mediated odontogenesis.MethodsPutative miR-335-3p/miR-155-5p binding sites within IGFBP7-AS1 were identified by bioinformatics analysis, and the binding of miR-335-3p/miR-155-5p to these sites was confirmed by dual-luciferase reporter gene assays. The effects of miR-335-3p/miR-155-5p in odontogenesis were detected by tissue nonspecific alkaline phosphatase staining, Alizarin red staining, quantitative real-time polymerase chain reaction (qRT-PCR) analyses, and western blot testing. The molecular mechanisms of miR-335-3p/miR-155-5p involved in IGFBP7-AS1-mediated odontogenesis were analysed by qRT-PCR and western blot testing.ResultsDual-luciferase reporter gene assays showed that miR-335-3p/miR-155-5p could directly bind to IGFBP7-AS1. MiR-335-3p and miR-155-5p both could down-regulate dentin sialophosphoprotein expression, and both miRNAs could inhibit IGFBP7-AS1-mediated SHED odontogenetic differentiation via suppression of the extracellular signal-regulated kinase (ERK) pathway.ConclusionsBoth miR-335-3p and miR-155-5p were negative regulators to IGFBP7-AS1-enhanced odontogenic differentiation of SHED through suppression of the ERK pathway.

Dataset Information

Brucella Omp25 Upregulates miR-155, miR-21-5p, and miR-23b to Inhibit Interleukin-12 Production via Modulation of Programmed Death-1 Signaling in Human Monocyte/Macrophages.

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<i>Brucella</i> Omp25 Upregulates miR-155, miR-21-5p, and miR-23b to Inhibit Interleukin-12 Production <i>via</i> Modulation of Programmed Death-1 Signaling in Human Monocyte/Macrophages.

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