Hsa_circ_0004287 通过依赖 m6A 的方式抑制特应性皮炎和银屑病中巨噬细胞介导的炎症。
Hsa_circ_0004287 inhibits macrophage-mediated inflammation in an N-methyladenosine-dependent manner in atopic dermatitis and psoriasis.
机构信息
Institute of Pediatrics, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China; National Health Commission Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China.
Institute of Pediatrics, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Department of General Medicine, Children's Hospital of Fudan University, Shanghai, China.
出版信息
J Allergy Clin Immunol. 2022 Jun;149(6):2021-2033. doi: 10.1016/j.jaci.2021.11.024. Epub 2021 Dec 23.
BACKGROUND
Circular RNA (circRNA) has been implicated in various diseases; however, its role in atopic dermatitis (AD) or psoriasis remains unclear.
OBJECTIVE
We sought to determine the differential expression profiles of circRNAs in peripheral blood mononuclear cells between healthy controls and AD patients, and explore the mechanisms underlying the effects of circRNAs on the pathogenesis of AD.
METHODS
The differential expression profiles of circRNAs were analyzed by circRNA microarray. In vitro function and mechanisms by which circRNAs regulate macrophage-mediated inflammation were detected by reverse transcription quantitative PCR, Western blot analysis, RNA stability assay, immunoprecipitation, ELISA, and methylated RNA immunoprecipitation assay. In vivo roles of circRNAs were determined in 2,4-dinitrochlorobenzene (DNCB)-induced dermatitis and imiquimod (IMQ)-induced psoriasis mouse model.
RESULTS
We identified a functional unknown circRNA hsa_circ_0004287 from 88750 circRNAs, which was upregulated in peripheral blood mononuclear cells of both AD and psoriasis patients, and was mainly expressed by macrophages under inflammatory conditions. Hsa_circ_0004287 inhibited M1 macrophage activation in vitro, and macrophage-specific overexpression of hsa_circ_0004287 alleviated skin inflammation in both AD- and psoriasis-like mice. Mechanistically, hsa_circ_0004287 reduced the stability of its host gene metastasis associated lung adenocarcinoma transcript 1 (MALAT1) by competitively binding to IGF2BP3 with MALAT1 in an N-methyladenosine (mA)-dependent manner. Lower levels of MALAT1 promoted the ubiquitination degradation of S100A8/S100A9, thereby impeding p38/mitogen-activated protein kinase phosphorylation and macrophage-mediated inflammation.
CONCLUSION
hsa_circ_0004287 inhibits M1 macrophage activation in an mA-dependent manner in AD and psoriasis, and may serve as a general therapeutic candidate for AD and psoriasis.
背景
环状 RNA（circRNA）与多种疾病有关；然而，其在特应性皮炎（AD）或银屑病中的作用尚不清楚。
目的
我们旨在确定健康对照者和 AD 患者外周血单个核细胞中 circRNA 的差异表达谱，并探讨 circRNA 对 AD 发病机制影响的机制。
方法
通过 circRNA 微阵列分析 circRNA 的差异表达谱。通过逆转录定量 PCR、Western blot 分析、RNA 稳定性测定、免疫沉淀、ELISA 和甲基化 RNA 免疫沉淀测定检测 circRNA 调节巨噬细胞介导的炎症的体外功能和机制。通过 2,4-二硝基氯苯（DNCB）诱导的皮炎和咪喹莫特（IMQ）诱导的银屑病小鼠模型确定 circRNA 的体内作用。
结果
我们从 88750 个 circRNAs 中鉴定出一个功能未知的 circRNA hsa_circ_0004287，其在外周血单个核细胞中在 AD 和银屑病患者中均上调，并且在炎症条件下主要由巨噬细胞表达。Hsa_circ_0004287 在体外抑制 M1 巨噬细胞活化，并且巨噬细胞特异性过表达 hsa_circ_0004287 减轻 AD 和银屑病样小鼠的皮肤炎症。在机制上，hsa_circ_0004287 通过与 MALAT1 竞争结合 IGF2BP3 以 mA 依赖性方式降低其宿主基因转移相关肺腺癌转录物 1（MALAT1）的稳定性。较低水平的 MALAT1 促进 S100A8/S100A9 的泛素化降解，从而阻止 p38/丝裂原活化蛋白激酶磷酸化和巨噬细胞介导的炎症。
结论
hsa_circ_0004287 以 mA 依赖性方式抑制 AD 和银屑病中的 M1 巨噬细胞活化，可作为 AD 和银屑病的一般治疗候选物。
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