USP18 诱导调节免疫代谢,以削弱系统性红斑狼疮中 M1 信号极化的巨噬细胞并增强 IL-4 极化的巨噬细胞。

IF 4.5 3区 医学 Q2 IMMUNOLOGY Clinical immunology Pub Date : 2024-06-14 DOI:10.1016/j.clim.2024.110285
Jenn-Haung Lai , De-Wei Wu , Chuan-Yueh Huang , Li-Feng Hung , Chien-Hsiang Wu , Ling-Jun Ho
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引用次数: 0

摘要

系统性红斑狼疮(SLE)的有效治疗仍是一项尚未满足的需求。巨噬细胞的不同亚群在系统性红斑狼疮中发挥着不同的作用,而调节巨噬细胞的极化,使其脱离 M1 状态,对系统性红斑狼疮的治疗是有益的。鉴于 I 型干扰素(IFN-I)在系统性红斑狼疮中的致病作用,本研究调查了线粒体定位分子泛素特异性肽酶 18(USP18)保留抗 IFN 作用和异肽酶活性对巨噬细胞极化的影响和机制。在观察了 USP18 在系统性红斑狼疮患者单核细胞中的诱导作用后,我们对小鼠骨髓衍生巨噬细胞进行了研究,结果表明 USP18 缺乏会增加 M1 信号(LPS + IFN-γ 处理)诱导的巨噬细胞极化,其影响涉及糖酵解和线粒体呼吸的诱导以及多种糖酵解相关酶和分子(如缺氧诱导因子-1α)的表达。此外,还观察到对线粒体活性的影响,如线粒体 DNA 释放和线粒体活性氧的产生。相反,USP18 的过表达抑制了 M1 信号介导的巨噬细胞极化,增强了白细胞介素-4(IL-4)介导的巨噬细胞极化及相关细胞事件。此外,USP18 mRNA 的表达水平与系统性红斑狼疮患者单核细胞中代谢酶的表达呈相关趋势。我们由此得出结论,通过保持抗IFN效应和下调M1信号,促进USP18的活性可作为系统性红斑狼疮治疗的一种有效方法。
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USP18 induction regulates immunometabolism to attenuate M1 signal-polarized macrophages and enhance IL-4-polarized macrophages in systemic lupus erythematosus

Effective treatment of systemic lupus erythematosus (SLE) remains an unmet need. Different subsets of macrophages play differential roles in SLE and the modulation of macrophage polarization away from M1 status is beneficial for SLE therapeutics. Given the pathogenic roles of type I interferons (IFN-I) in SLE, this study investigated the effects and mechanisms of a mitochondria localization molecule ubiquitin specific peptidase 18 (USP18) preserving anti-IFN effects and isopeptidase activity on macrophage polarization. After observing USP18 induction in monocytes from SLE patients, we studied mouse bone marrow-derived macrophages and showed that USP18 deficiency increased M1signal (LPS + IFN-γ treatment)-induced macrophage polarization, and the effects involved the induction of glycolysis and mitochondrial respiration and the expression of several glycolysis-associated enzymes and molecules, such as hypoxia-inducible factor-1α. Moreover, the effects on mitochondrial activities, such as mitochondrial DNA release and mitochondrial reactive oxygen species production were observed. In contrast, the overexpression of USP18 inhibited M1signal-mediated and enhanced interleukin-4 (IL-4)-mediated polarization of macrophages and the related cellular events. Moreover, the levels of USP18 mRNA expression showed tendency of correlation with the expression of metabolic enzymes in monocytes from patients with SLE. We thus concluded that by preserving anti-IFN effect and downregulating M1 signaling, promoting USP18 activity may serve as a useful approach for SLE therapeutics.

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来源期刊
Clinical immunology
Clinical immunology 医学-免疫学
CiteScore
12.30
自引率
1.20%
发文量
212
审稿时长
34 days
期刊介绍: Clinical Immunology publishes original research delving into the molecular and cellular foundations of immunological diseases. Additionally, the journal includes reviews covering timely subjects in basic immunology, along with case reports and letters to the editor.
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