Elevated microRNA-21 Is a Brake of Inflammation Involved in the Development of Nasal Polyps.
Elevated microRNA-21 Is a Brake of Inflammation Involved in the Development of Nasal Polyps.
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microRNA-21 升高是鼻息肉发展中炎症的阻碍因素
DOI：
10.3389/fimmu.2021.530488
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发表时间：
2021
影响因子：
7.3
通讯作者：
Liu S
中科院分区：
文献类型：
--
作者：
Liu R;Du J;Zhou J;Zhong B;Ba L;Zhang J;Liu Y;Liu S
CRSwNP是一种炎症性疾病，但其机制尚未完全了解。MiR-21是miRNAs的成员之一，已被报道在介导炎症中发挥作用。然而，miR-21的表达及其在CRSwNP患者中的作用仍然难以捉摸。收集来自对照受试者的鼻甲、来自CRSsNP的钩突、来自CRSwNP的息肉组织和从鼻粘膜刷取的鼻上皮细胞。qPCR检测鼻黏膜组织和上皮细胞中miR-21和细胞因子的表达。采用原位杂交技术检测miR-21的定位，生物信息学分析、qPCR、免疫组化、WB、荧光素酶报告系统等方法鉴定miR-21的靶基因。转染miR-21后，用WB和qPCR检测PDCD 4和NF-κB P65蛋白和mRNA的表达。在HNEpC和鼻息肉外植体中分析miR-21对细胞因子的作用。通过qPCR，相对于对照受试者，CRSwNP中的MiR-21上调，这主要通过ISH在CRSwNP的鼻上皮细胞中确定。促炎细胞因子（IL-1β、IL-6、IL-8、IL-25和TSLP）和抑制性细胞因子（IL-10）在CRSwNP的上皮细胞中过表达。CRSwNP上皮细胞中miR-21的表达与IL-10呈正相关，与IL-6、IL-8、IL-33、TSLP呈负相关。PDCD 4作为miR-21的潜在靶点，在CRSwNP中的表达与miR-21呈负相关。在HNEpC中，miR-21可在mRNA和蛋白水平上降低PDCD 4的表达，生物信息学分析和荧光素酶报告系统证实PDCD 4是miR-21的作用靶点之一。miR-21可降低NF-κB的活化，增加IL-10 mRNA的表达。SEB和LPS均可上调miR-21的表达，SEB可诱导IL-25、IL-33、TSLP的表达，LPS可诱导IL-1β、IL-6、IL-8的表达，而miR-21在体外和离体均能调节IL-33、TSLP、IL-1β、IL- 6、IL-8的表达。临床上，miR-21表达与CRSwNP的Lund-Mackay CT评分和Lund-Kennedy评分呈负相关。miR-21可能是炎症过程中一个重要的负反馈因子，通过抑制促炎细胞因子的表达，从而在CRSwNP中发挥抗炎作用。
CRSwNP is an inflammatory disease but the mechanism is not yet fully understood. MiR-21, a member of miRNAs, has been reported to play roles in mediating inflammation. However, the expression of miR-21 and its role in patients with CRSwNP remain elusive. Turbinates from control subjects, uncinate processes from CRSsNP, polyp tissues from CRSwNP, and nasal epithelial cells brushed from nasal mucosa were collected. The expression of miR-21 and cytokines in nasal tissues and epithelial cells were detected by qPCR. The localization of miR-21 was detected by ISH, and its target was identified by bioinformation analysis, qPCR, IHC, WB, and luciferase reporter system. The protein and mRNA of PDCD4 and NF-κB P65 were determined by WB and qPCR after miR-21 transfection in HNEpC. The role of miR-21 on cytokines was analyzed in HNEpC and nasal polyp explants. MiR-21 was upregulated in CRSwNP relative to control subjects by qPCR, which was determined mainly in nasal epithelial cells of CRSwNP by ISH. Both pro-inflammation cytokines (IL-1β, IL-6, IL-8, IL-25, and TSLP) and a suppressive cytokine (IL-10) were overexpressed in the epithelial cells of CRSwNP. The expression of miR-21 was positively correlated with IL-10 and negatively correlated with IL-6, IL-8, IL-33, and TSLP in the epithelial cells of CRSwNP. As a potential target of miR-21, the expression of PDCD4 was negatively correlated with miR-21 in CRSwNP. In HNEpC, miR-21 could reduce the expression of PDCD4 at both mRNA and protein levels, and bioinformation analysis and luciferase reporter system confirmed PDCD4 as one target of miR-21. Furthermore, miR-21 could decrease the activation of NF-κB and increase IL-10 mRNA. Both SEB and LPS could elevate miR-21, with IL-25, IL-33, TSLP induced by SEB and IL-1β, IL-6, IL-8 induced by LPS, while the miR-21 could regulate the expression of IL-33, TSLP, IL-1β, IL- 6 and IL-8 in vitro and ex vivo. Clinically, miR-21 expression was inversely correlated with the Lund-Mackay CT scores and the Lund-Kennedy scores in CRSwNP. MiR-21 could be a prominent negative feedback factor in the inflammation process to attenuate the expression of pro-inflammatory cytokines, thereby playing an anti-inflammation role in CRSwNP.