IRF4 转录激活 HOTAIRM1，HOTAIRM1 反过来又调节 IRF4 的表达，从而影响 Th9 细胞分化，并参与变应性鼻炎。
IRF4 transcriptionally activate HOTAIRM1, which in turn regulates IRF4 expression, thereby affecting Th9 cell differentiation and involved in allergic rhinitis.
机构信息
Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, People's Republic of China.
Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, People's Republic of China.
出版信息
Gene. 2022 Mar 1;813:146118. doi: 10.1016/j.gene.2021.146118. Epub 2021 Dec 18.
BACKGROUND
Allergic rhinitis (AR) is an inflammatory reaction caused by irritation of nasal mucosa by external allergens, which seriously affects the life of patients. Here, we aimed to investigate the effect and mechanism of long non-coding RNA HOX antisense intergenic RNA myeloid 1 (lncRNA HOTAIRM1) on AR development.
METHODS
The nasal mucosa samples were collected from AR patients and AR model mice (induced by ovalbumin). T helper type 9 (Th9) cells were examined by flow cytometry. Fluorescence in situ hybridization was conducted to examine the localization of HOTAIRM1 in CD4 T cells. Dual-luciferase reporter assay or RNA immunoprecipitation was conducted to examine the bond between HOTAIRM1 and miR-148a-3p, miR-148a-3p, and interferon regulatory factor 4 (IRF4). Chromatin Immunoprecipitation assay was conducted to detect the interaction between IRF4 and HOTAIRM1 promoter.
RESULTS
HOTAIRM1, interleukin-9 (IL-9), and IRF4 were highly expressed in the AR model. The ratio of Th9 cells was increased in AR mice and overexpressing HOTAIRM1 further promoted Th9 cell differentiation, while the effect was reversed after overexpression of miR-148a-3p. Besides, in vivo experiments showed that interfering with HOTAIRM1 reduced the number of sneezing and rubbing movements, reduced immunoglobulin E (IgE) and IL-9 levels, as well as Th9 cells. HOTAIRM1 was expressed in the cytoplasm and the interactions between HOTAIRM1 and miR-148a-3p, miR-148a-3p and IRF4, were confirmed. Furthermore, IRF4 bound to the HOTAIRM1 promoter and promoted its transcriptional activation.
CONCLUSION
HOTAIRM1 was highly expressed in the AR model. Besides, IRF4 activated HOTAIRM1 transcription, and HOTAIRM1, in turn, up-regulated IRF4 expression through competitively binding to miR-148a-3p with IRF4, thereby affecting Th9 cell differentiation and participating in the occurrence and development of AR. Our results suggested that interference with HOTAIRM1 might become a treatment for AR.
背景
变应性鼻炎（AR）是由鼻黏膜对外源性过敏原刺激引起的炎症反应，严重影响患者的生活。在这里，我们旨在研究长链非编码 RNA HOX 反义基因间 RNA 髓系 1（lncRNA HOTAIRM1）对 AR 发展的影响和机制。
方法
收集 AR 患者和卵清蛋白诱导的 AR 模型小鼠的鼻黏膜样本。采用流式细胞术检测 Th9 细胞。采用荧光原位杂交检测 CD4 T 细胞中 HOTAIRM1 的定位。采用双荧光素酶报告基因检测或 RNA 免疫沉淀检测 HOTAIRM1 与 miR-148a-3p、miR-148a-3p 与干扰素调节因子 4（IRF4）的结合。采用染色质免疫沉淀检测 IRF4 与 HOTAIRM1 启动子的相互作用。
结果
在 AR 模型中，HOTAIRM1、白细胞介素-9（IL-9）和 IRF4 表达水平升高。在 AR 小鼠中，Th9 细胞比例增加，而过表达 HOTAIRM1 进一步促进 Th9 细胞分化，而转染 miR-148a-3p 后则逆转了这一作用。此外，体内实验表明，干扰 HOTAIRM1 可减少喷嚏和搔抓次数，降低免疫球蛋白 E（IgE）和 IL-9 水平以及 Th9 细胞数量。HOTAIRM1 在细胞质中表达，并证实了 HOTAIRM1 与 miR-148a-3p、miR-148a-3p 与 IRF4 之间的相互作用。此外，IRF4 结合到 HOTAIRM1 启动子上并促进其转录激活。
结论
AR 模型中 HOTAIRM1 表达水平升高。此外，IRF4 激活 HOTAIRM1 转录，而 HOTAIRM1 则通过与 IRF4 竞争结合 miR-148a-3p 来上调 IRF4 的表达，从而影响 Th9 细胞分化并参与 AR 的发生和发展。我们的研究结果表明，干扰 HOTAIRM1 可能成为 AR 的一种治疗方法。
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