Reactive Oxygen Species-Mediated TRPM2 Activation Facilitates Phagocytosis of Macrophages to Reverse Profibrotic Phenotype

IF 5.2 2区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Liver International Pub Date : 2025-09-15 DOI:10.1111/liv.70341

Shaoying Zhang, Fanfan Liang, Dan Wan, Chongyu Zhang, Yinggang Zhang, Xurui Zhang, Na Huang, Keping Feng, Xiao Liang, Ni Guo, Chen Zhang, Zhe Zhou, Yuehua Li, Jing Geng, Pengfei Liu, Guangyao Kong, Shemin Lu, Zongfang Li

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引用次数: 0

Abstract

Background and Aims

Macrophages play plastic roles during fibrogenesis and fibrosis regression. Phagocytosis is considered a trigger for shifting macrophages from a profibrotic phenotype to a restorative phenotype. However, the underlying mechanism by which macrophages enhance phagocytosis remains unclear. Our present study investigated the role of reactive oxygen species (ROS)-modulated TRPM2 activation in this process.

Methods

The changes of TRPM2 expression, ROS intensity, and macrophage phagocytosis were assessed in fibrogenesis and fibrosis regression models. RNA sequencing was utilised to reveal pathway enrichment caused by TRPM2, and the role of TRPM2 in enhancing phagocytosis was verified. The coordinate regulation of ROS-TRPM2 in different functions of macrophages was demonstrated by modulating ROS intensity and TRPM2 expression. Mitochondrial dynamics changes induced by ROS-stimulated TRPM2 activation were evaluated by analysing the expression of dynamics-related molecules and mitochondrial imaging, and intervention in mitochondrial dynamics confirmed their impact on macrophage phagocytosis.

Results

Low-intensity ROS stimulation up-regulated the expression of TRPM2 and coordinately enhanced macrophage phagocytosis and the expression of matrix degradation-related proteins (MMPs), a process akin to fibrosis regression. However, high-intensity ROS inclined macrophages to produce more profibrotic cytokines, associating with oxidative stress caused by liver injury. ROS-mediated TRPM2 activation mobilised Ca²⁺ and promoted mitochondrial fission; either inhibiting mitochondrial fission or chelating Ca²⁺ counteracted phagocytosis, as well as decreasing MMPs.

Conclusions

ROS-TRPM2 coordinately regulate macrophage functions. During the liver fibrosis regression period, ROS-induced activation of TRPM2 helps enhance macrophage phagocytosis and switches them to a restorative phenotype. Modulating this process may provide means for developing effective therapeutic strategies.

Abstract Image

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活性氧介导的TRPM2激活促进巨噬细胞吞噬逆转纤维化表型

背景与目的巨噬细胞在纤维化发生和纤维化消退过程中起着可塑性作用。吞噬作用被认为是巨噬细胞从纤维化表型向恢复性表型转移的触发因素。然而，巨噬细胞增强吞噬作用的潜在机制尚不清楚。我们目前的研究探讨了活性氧（ROS）调节的TRPM2激活在这一过程中的作用。方法在纤维化和纤维化回归模型中观察TRPM2表达、ROS强度和巨噬细胞吞噬的变化。利用RNA测序揭示了TRPM2引起的途径富集，并验证了TRPM2增强吞噬的作用。通过调节ROS强度和TRPM2的表达，证明了ROS-TRPM2在巨噬细胞不同功能中的协同调节作用。通过分析动力学相关分子的表达和线粒体成像来评估ros刺激TRPM2激活引起的线粒体动力学变化，对线粒体动力学的干预证实了其对巨噬细胞吞噬的影响。结果低强度的ROS刺激上调TRPM2的表达，并协同增强巨噬细胞吞噬和基质降解相关蛋白（matrix降解-related protein， MMPs）的表达，这一过程类似于纤维化消退。然而，高强度ROS倾向巨噬细胞产生更多促纤维化细胞因子，与氧化应激引起的肝损伤有关。ros介导的TRPM2活化调动Ca2+，促进线粒体裂变；抑制线粒体分裂或螯合Ca2+抵消吞噬作用，以及降低MMPs。结论ROS-TRPM2可协调调节巨噬细胞功能。在肝纤维化消退期，ros诱导的TRPM2激活有助于增强巨噬细胞的吞噬作用，并将巨噬细胞转换为恢复性表型。调节这一过程可能为开发有效的治疗策略提供手段。

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

Liver International 医学-胃肠肝病学

CiteScore

13.90

自引率

4.50%

发文量

348

审稿时长

2 months

期刊介绍： Liver International promotes all aspects of the science of hepatology from basic research to applied clinical studies. Providing an international forum for the publication of high-quality original research in hepatology, it is an essential resource for everyone working on normal and abnormal structure and function in the liver and its constituent cells, including clinicians and basic scientists involved in the multi-disciplinary field of hepatology. The journal welcomes articles from all fields of hepatology, which may be published as original articles, brief definitive reports, reviews, mini-reviews, images in hepatology and letters to the Editor.