MiR-382-5p suppresses M1 macrophage polarization and inflammatory response in response to bronchopulmonary dysplasia through targeting CDK8: Involving inhibition of STAT1 pathway,Genes to Cells

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MiR-382-5p suppresses M1 macrophage polarization and inflammatory response in response to bronchopulmonary dysplasia through targeting CDK8: Involving inhibition of STAT1 pathway
Genes to Cells ( IF 1.3 ) Pub Date : 2021-07-06 , DOI: 10.1111/gtc.12883
Yuanyuan Lv _{1,

2} , Yang Li ₁ , Jiangya Wang ₃ , Mei Li ₁ , Wenhao Zhang ₁ , Huifen Zhang ₁ , Ying Shen ₁ , Chao Li ₂ , Yuan Du ₄ , Lian Jiang ₁

Affiliation

Bronchopulmonary dysplasia (BPD) is an inflammation-related respiratory disorder in infants. MiR-382-5p has displayed low expression in developing lungs with BPD, while the effect of miR-382-5p on BPD remains elusive. Here, a hyperoxia (85% oxygen)-induced BPD model in neonatal mice was established. On postnatal days 10 and 15, hyperoxia reduced miR-382-5p expression in lungs of mice. Besides, CDK8, CD68 and CD86 levels were elevated on day 15 after birth, implying the involvement of CDK8 in M1 macrophage polarization. In addition, in vitro injury in RAW264.7 macrophages was induced by IFN-γ and LPS stimulation. Lentivirus-encoding miR-382-5p decreased CDK8 expression, alleviated the production of inflammatory cytokines TNF-α, IL-1β and IL-6, and restricted the levels of CD40 and CD86 in response to IFN-γ and LPS. Moreover, miR-382-5p inhibited the phosphorylation of STAT1. Luciferase reporter assay verified that miR-382-5p might target the 3′UTR of CDK8. Rescue assays revealed that CDK8 reversed the mitigating roles of miR-382-5p in inflammatory response and M1 macrophage polarization, as reflected by increased IL-6 and CD40 levels. Taken together, these findings indicate that miR-382-5p may suppress M1 macrophage activation and inflammatory response via inhibiting CDK8, thereby regulating the development of BPD, which is possibly mediated by STAT1 signaling.

中文翻译：

MiR-382-5p 通过靶向 CDK8 抑制 M1 巨噬细胞极化和炎症反应以应对支气管肺发育不良：涉及抑制 STAT1 通路

支气管肺发育不良 (BPD) 是一种与炎症相关的婴儿呼吸系统疾病。miR-382-5p 在患有 BPD 的发育中的肺中表现出低表达，而 miR-382-5p 对 BPD 的影响仍然难以捉摸。在这里，建立了新生小鼠中高氧（85% 氧气）诱导的 BPD 模型。在出生后第 10 天和第 15 天，高氧降低了小鼠肺中 miR-382-5p 的表达。此外，CDK8、CD68和CD86水平在出生后第15天升高，提示CDK8参与了M1巨噬细胞极化。此外，在 RAW264.7 巨噬细胞中的体外损伤是由 IFN-γ 和 LPS 刺激诱导的。慢病毒编码 miR-382-5p 降低 CDK8 表达，减轻炎症细胞因子 TNF-α、IL-1β 和 IL-6 的产生，并限制 CD40 和 CD86 的水平以响应 IFN-γ 和 LPS。而且，miR-382-5p 抑制 STAT1 的磷酸化。荧光素酶报告基因分析证实 miR-382-5p 可能靶向 CDK8 的 3'UTR。救援分析显示，CDK8 逆转了 miR-382-5p 在炎症反应和 M1 巨噬细胞极化中的缓解作用，这反映在 IL-6 和 CD40 水平升高。总之，这些发现表明 miR-382-5p 可能通过抑制 CDK8 来抑制 M1 巨噬细胞活化和炎症反应，从而调节 BPD 的发展，这可能是由 STAT1 信号传导介导的。

更新日期：2021-07-06

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