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.
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.
复制标题
布鲁氏菌 Omp25 通过调节人单核细胞/巨噬细胞中的程序性死亡 1 信号传导上调 miR-155、miR-21-5p 和 miR-23b 以抑制 Interleukin-12 的产生
DOI：
10.3389/fimmu.2017.00708
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发表时间：
2017
影响因子：
7.3
通讯作者：
Huang Y
中科院分区：
文献类型：
--
作者：
Cui B;Liu W;Wang X;Chen Y;Du Q;Zhao X;Zhang H;Liu SL;Tong D;Huang Y
布鲁氏菌感染导致受损的1型（Th 1）细胞免疫应答。一些报道描述了布鲁氏菌外膜蛋白Omp 25的免疫调节功能。然而，Omp 25调节巨噬细胞功能障碍的机制尚未确定。在此，我们报道了Omp 25缺陷型猪布鲁氏菌突变体表现出增强的诱导白细胞介素（IL）-12的能力，而Omp 25蛋白的异位表达通过抑制THP-1细胞中IL-12 p40和p35亚基的表达来抑制TLR激动剂诱导的IL-12 p70的产生。此外，Omp 25显著上调单核细胞/巨噬细胞中的miR-155、-23 b和-21-5 p以及免疫调节剂分子程序性死亡-1（PD-1）。miR-155和-23 B的上调分别通过靶向TAB 2和il 12 B 3′非翻译区（UTR）而与TAB 2水平、IκB磷酸化和IL-12 p40水平的降低在时间上相关，而miR-21- 5 p的上调通过靶向il 12 A 3′UTR而直接导致脂多糖（LPS）/R848诱导的IL-12 p35蛋白的降低。与这一发现一致，miR-155和-23 b的减少在转录和转录后水平上减弱了Omp 25对LPS/R848诱导的IL-12 p40表达的抑制作用，而miR-21- 5 p的减少在转录后水平上减弱了Omp 25对LPS/R848诱导的IL-12 p35表达的抑制作用，在LPS/R848刺激后，两者一起显著增强IL-12 p70的产生。我们还发现阻断PD-1信号传导降低了Omp 25诱导的miR-155、-23b和-21-5p的表达，并增强了单核细胞/巨噬细胞中的IL-12产生。总之，这些数据表明，布鲁氏菌Omp 25诱导miR-155、-23b和-21-5p通过调节PD-1信号传导在转录和转录后水平负调节IL-12产生，这提供了布鲁氏菌属期间单核细胞/巨噬细胞功能障碍的全新机制。感染
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, IκB 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.