IF 3.7 4区 医学 Q2 CELL BIOLOGY
Aizhi Zhang , Huanping Zhang , Le Liu , Hanqing Zhang , Lihua Mo , Wenkai Zhang , Hanis Hazeera Harith , Liying Cheng , Jieping Lv , Chau Ling Tham , Pingchang Yang
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引用次数: 0

摘要

树突状细胞(DC)功能失调会导致许多免疫疾病。其机理尚未完全阐明。本研究旨在调控赖氨酸特异性去甲基化酶4D(KDM4D)的表观遗传学状态,以增强树突状细胞的免疫耐受能力。本研究以尘螨提取物(DME)为特异性抗原,建立了气道过敏(AA)小鼠模型。实验采用了携带 Kdm4d 缺陷 DCs 的小鼠品系,以评估 KDM4D 在调节 DC 免疫耐受功能中的作用。结果显示,携带Kdm4d缺陷DCs的小鼠(KO小鼠)在气道中表现出自发的Th2极化。在 AA 小鼠的气道幼稚 DCs(nDCs)中检测到的 KDM4D 数量减少。AA 反应的参数与 KDM4D 的数量呈负相关。KO小鼠和AA小鼠气道nDCs的免疫耐受能力均受损。在AA小鼠和KO小鼠的气道nDCs中,Il10启动子被高甲基化。在 AA 小鼠气道 nDCs 的 Il10 启动子位点中,去泛素化酶 14(USP14)的数量较少,这与 KDM4D 中观察到的高水平超泛素化有关。暴露于重组 USP14 会增加 nDCs 中 KDM4D 的数量,从而恢复 AA 小鼠 nDCs 的免疫耐受能力。总之,AA 小鼠气道 nDC 中低水平的 KDM4D 导致了耐受性失调。USP14 恢复了 AA 小鼠 nDCs 的耐受能力,减轻了实验性 AA 的病情。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
USP14 inhibits sensitization-mediated degradation of KDM4D to epigenetically regulate dendritic cell tolerogenic capacity and mitigates airway allergy
Numerous immune disorders are caused by the dysfunction of dendritic cells (DC). The mechanism has not been fully comprehended yet. This research is designed to regulate the epigenetic status of lysine-specific demethylase 4D (KDM4D) to enhance DC's immune tolerogenic capacity. In this study, an airway allergy (AA) mouse model was established with dust mite extracts (DME) as the specific antigen. A mouse strain carrying Kdm4d-deficient DCs was employed in the experiments to assess the role of KDM4D in modulating DC's immune tolerogenic functions. The results showed that mice carrying Kdm4d-deficient DCs (KO mice) showed spontaneous Th2 polarization in the airways. Reduced quantities of KDM4D were detected in airway naive DCs (nDCs) of AA mice. The parameters of AA response had a negative correlation with the quantity of KDM4D. The immune tolerogenic capacity of airway nDCs was impaired in KO mice as well as in AA mice. The Il10 promoter was found to be hypermethylated in airway nDCs of AA mice and KO mice. The low quantity of deubiquitinating enzyme 14 (USP14) was related to the high level of hyper ubiquitination observed in KDM4D in the Il10 promoter locus of airway nDCs of AA mice. Exposure to recombinant USP14 increased the quantity of KDM4D in nDCs, restoring the immune tolerogenic capacity of nDCs in AA mice. In conclusion, dysfunctional tolerogenicity is caused by low levels of KDM4D in airway nDCs from AA mice. USP14 restores the tolerogenic capacity of nDCs in AA mice and mitigates experimental AA.
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来源期刊
Cellular immunology
Cellular immunology 生物-免疫学
CiteScore
8.20
自引率
2.30%
发文量
102
审稿时长
30 days
期刊介绍: Cellular Immunology publishes original investigations concerned with the immunological activities of cells in experimental or clinical situations. The scope of the journal encompasses the broad area of in vitro and in vivo studies of cellular immune responses. Purely clinical descriptive studies are not considered. Research Areas include: • Antigen receptor sites • Autoimmunity • Delayed-type hypersensitivity or cellular immunity • Immunologic deficiency states and their reconstitution • Immunologic surveillance and tumor immunity • Immunomodulation • Immunotherapy • Lymphokines and cytokines • Nonantibody immunity • Parasite immunology • Resistance to intracellular microbial and viral infection • Thymus and lymphocyte immunobiology • Transplantation immunology • Tumor immunity.
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