高糖通过肺泡巨噬细胞中的环境细颗粒物增强NLRP3炎症小体的激活。

IF 7.2 1区 医学 Q1 TOXICOLOGY Particle and Fibre Toxicology Pub Date : 2023-11-02 DOI:10.1186/s12989-023-00552-8
Yiqun Mo, Luke Mo, Yue Zhang, Yuanbao Zhang, Jiali Yuan, Qunwei Zhang
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引用次数: 0

摘要

背景:流行病学研究表明,包括糖尿病在内的已有疾病的人更容易受到空气污染的影响。然而,其根本机制仍不清楚。在这项研究中,我们提出,高糖环境通过激活NLRP3炎症小体,增强环境细颗粒物(PM2.5)诱导的巨噬细胞活化和促炎细胞因子IL-1β的分泌,改变基质金属蛋白酶(MMPs)和MMPs组织抑制剂(TIMPs)之间的平衡。结果:小鼠肺泡巨噬细胞暴露于非细胞毒性剂量的PM2.5导致IL-1β上调,NLRP3炎症小体激活,转录因子NF-κB的核转位增加,活性氧(ROS)的产生增加,以及增加MMP-9的表达和酶活性;当用高糖预处理细胞时,这些作用增强。然而,单独在高糖环境中预处理并没有引起显著的变化。当用ROS清除剂如Trolox和超氧化物歧化酶(SOD)或NADPH氧化酶抑制剂DPI预处理细胞时,PM2.5暴露后的ROS产生被消除。DPI预处理细胞减弱了高糖对PM2.5诱导的IL-1β上调、NLRP3炎症小体激活和NF-κB核转位的影响。此外,在从NLRP3或IL-1R1敲除(KO)小鼠获得的原代肺泡巨噬细胞中,未观察到高糖预处理后PM2.5诱导的MMP-9表达和酶活性的增强,其中pro-IL-1β不能分别切割为IL-1β或细胞对IL-1β不敏感。结论:本研究表明,小鼠肺泡巨噬细胞在高糖环境中暴露于PM2.5,通过激活NLRP3炎症小体和PM2.5诱导的氧化应激引起的NF-κB核转位,增强了PM2.5诱导IL-1β的产生,导致MMP-9上调。还证明了NADPH氧化酶在PM2.5诱导的ROS产生和IL-1β分泌途径激活中的关键作用,以及IL-1β的分泌和信号传导在PM2.5导致的MMP-9酶活性增加中的重要性。这项研究进一步了解了糖尿病患者对空气污染易感性的潜在机制,并提出了潜在的治疗靶点。
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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High glucose enhances the activation of NLRP3 inflammasome by ambient fine particulate matter in alveolar macrophages.

Background: Epidemiological studies have demonstrated that individuals with preexisting conditions, including diabetes mellitus (DM), are more susceptible to air pollution. However, the underlying mechanisms remain unclear. In this study, we proposed that a high glucose setting enhances ambient fine particulate matter (PM2.5)-induced macrophage activation and secretion of the proinflammatory cytokine, IL-1β, through activation of the NLRP3 inflammasome, altering the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs).

Results: Exposure of mouse alveolar macrophages to non-cytotoxic doses of PM2.5 led to upregulation of IL-1β, activation of the NLRP3 inflammasome, increased nuclear translocation of the transcription factor NF-κB, increased generation of reactive oxygen species (ROS), and increased expression and enzymatic activity of MMP-9; these effects were enhanced when cells were pretreated with high glucose. However, pretreatment in a high glucose setting alone did not induce significant changes. ROS generation following PM2.5 exposure was abolished when cells were pretreated with ROS scavengers such as Trolox and superoxide dismutase (SOD), or with an NADPH oxidase inhibitor, DPI. Pretreatment of cells with DPI attenuated the effects of a high glucose setting on PM2.5-induced upregulation of IL-1β, activation of the NLRP3 inflammasome, and nuclear translocation of NF-κB. In addition, enhancement of PM2.5-induced expression and enzymatic activity of MMP-9 following high glucose pretreatment was not observed in primary alveolar macrophages obtained from NLRP3 or IL-1R1 knockout (KO) mice, where pro-IL-1β cannot be cleaved to IL-1β or cells are insensitive to IL-1β, respectively.

Conclusions: This study demonstrated that exposure of mouse alveolar macrophages to PM2.5 in a high glucose setting enhanced PM2.5-induced production of IL-1β through activation of the NLRP3 inflammasome and nuclear translocation of NF-κB due to PM2.5-induced oxidative stress, leading to MMP-9 upregulation. The key role of NADPH oxidase in PM2.5-induced ROS generation and activation of the IL-1β secretion pathway and the importance of IL-1β secretion and signaling in PM2.5-induced increases in MMP-9 enzymatic activity were also demonstrated. This study provides a further understanding of the potential mechanisms underlying the susceptibility of individuals with DM to air pollution and suggests potential therapeutic targets.

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来源期刊
CiteScore
15.90
自引率
4.00%
发文量
69
审稿时长
6 months
期刊介绍: Particle and Fibre Toxicology is an online journal that is open access and peer-reviewed. It covers a range of disciplines such as material science, biomaterials, and nanomedicine, focusing on the toxicological effects of particles and fibres. The journal serves as a platform for scientific debate and communication among toxicologists and scientists from different fields who work with particle and fibre materials. The main objective of the journal is to deepen our understanding of the physico-chemical properties of particles, their potential for human exposure, and the resulting biological effects. It also addresses regulatory issues related to particle exposure in workplaces and the general environment. Moreover, the journal recognizes that there are various situations where particles can pose a toxicological threat, such as the use of old materials in new applications or the introduction of new materials altogether. By encompassing all these disciplines, Particle and Fibre Toxicology provides a comprehensive source for research in this field.
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