Itaconate suppresses neonatal intestinal inflammation via metabolic reprogramming of M1 macrophage

IF 6.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-07-17 DOI:10.1002/ctm2.70419

Shuchen Huangfu, Chaoting Lan, Sitao Li, Huijuan Wang, Chun Yan, Yuling Yang, Bowen Tian, Yide Mu, Peizhi Zhao, Yan Tian, Yijia Wang, Wei Zhong, Limei Zhong, Yongyan Shi, Yufeng Liu

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引用次数: 0

Abstract

Background

Necrotizing enterocolitis (NEC) is a rapidly progressive and severe gastrointestinal disorder in neonates that is marked by an inflammatory cascade initiated by mechanisms that remain incompletely understood, resulting in intestinal necrosis and systemic infections. This study demonstrated that itaconate (ITA) exerts a protective effect in NEC by regulating macrophage reprogramming.

Methods

Changes in ITA expression were investigated using immunofluorescence staining and liquid chromatography-mass spectrometry, and their effect on immune cell differentiation was verified through single-cell sequencing. In vivo experiments were performed using ACOD1^−/- and ACOD1^fl/flLysM^cre NEC mouse models.

Results

We detected changes in ITA expression in clinical NEC samples and confirmed the effect of these changes on immune cell differentiation. In vivo experiments confirmed the therapeutic role of ITA in regulating macrophage differentiation in NEC, and we further investigated the mechanism by which ITA regulates macrophage metabolic reprogramming. The depletion of ITA in NEC correlates with an increased frequency of pro-inflammatory macrophage polarization, thereby exacerbating intestinal inflammatory injury. Importantly, our in vivo experiments revealed that treatment with 4-octyl itaconate (4OI) significantly mitigated intestinal symptoms associated with NEC in murine models. Mechanistic investigations showed that 4OI effectively suppressed M1 macrophage polarization by rescuing mitochondrial function and upregulating oxidative phosphorylation in macrophages.

Conclusions

Our results highlight ITA as a metabolic checkpoint of macrophage differentiation in NEC and suggest the therapeutic efficacy of 4OI in NEC.

Key points

Itaconate alleviates NEC by reprogramming M1 macrophage metabolism
ACOD1 deficiency exacerbates NEC severity
4OI maintains intestinal barrier integrity.
4OI rescues NEC by regulating macrophage mitochondrial activity.

Abstract Image

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衣康酸通过M1巨噬细胞代谢重编程抑制新生儿肠道炎症

坏死性小肠结肠炎（NEC）是新生儿中一种进展迅速的严重胃肠道疾病，其特征是炎症级联反应，其机制尚不完全清楚，可导致肠道坏死和全身性感染。本研究表明衣康酸（ITA）通过调节巨噬细胞重编程对NEC有保护作用。方法采用免疫荧光染色和液相色谱-质谱联用技术研究ITA表达的变化，并通过单细胞测序验证其对免疫细胞分化的影响。体内实验采用ACOD1−/-和ACOD1fl/flLysMcre NEC小鼠模型。结果我们检测到了临床NEC样本中ITA表达的变化，并证实了这些变化对免疫细胞分化的影响。体内实验证实了ITA调节NEC巨噬细胞分化的治疗作用，我们进一步探讨了ITA调节巨噬细胞代谢重编程的机制。NEC中ITA的缺失与促炎巨噬细胞极化频率增加相关，从而加剧肠道炎症损伤。重要的是，我们的体内实验显示，4-辛酯伊康酸（4OI）治疗可显著减轻小鼠模型中与NEC相关的肠道症状。机制研究表明，4OI通过挽救线粒体功能和上调巨噬细胞氧化磷酸化，有效抑制M1巨噬细胞极化。结论我们的研究结果突出了ITA作为NEC巨噬细胞分化的代谢检查点，并提示了4OI在NEC的治疗效果。Itaconate通过重编程M1巨噬细胞代谢减轻NEC ACOD1缺乏加重NEC严重程度4OI维持肠屏障完整性。4OI通过调节巨噬细胞线粒体活性来拯救NEC。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.