Role of cuproptosis in mediating the severity of experimental malaria-associated acute lung injury/acute respiratory distress syndrome.

IF 3 2区 医学 Q1 PARASITOLOGY
Xinpeng Hou, Tingting Zhou, Qi Wang, Pinru Chen, Min Zhang, Lirong Wu, Wenbin Liu, Xiaobao Jin, Zhenlong Liu, Hua Li, Bo Huang
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引用次数: 0

Abstract

Background: Malaria-associated acute lung injury/acute respiratory distress syndrome (MA-ALI/ARDS) is a fatal complication of Plasmodium falciparum infection that is partially triggered by macrophage recruitment and polarization. As reported, copper exposure increases the risk of malaria infection, and copper accumulation-induced cuproptosis triggers M1 macrophage polarization. It is thus hypothesized that cuproptosis could act as a critical mediator in the pathogenesis of MA-ALI/ARDS, but its underlying mechanism remains unclear. The present study aimed to explore the role of cuproptosis in the severity of murine MA-ALI/ARDS.

Methods: We utilized an experimental model of MA-ALI/ARDS using female C57BL/6 mice with P. berghei ANKA infection, and treated these animals with the potent copper ion carrier disulfiram (DSF) or copper ion chelator tetrathiomolybdate (TTM). The RAW 264.7 macrophages, which were stimulated with infected red blood cells (iRBCs) in vitro, were also targeted with DSF-CuCl2 or TTM-CuCl2 to further investigate the underlying mechanism.

Results: Our findings showed a dramatic elevation in the amount of copper and the expression of SLC31A1 (a copper influx transporter) and FDX1 (a key positive regulator of cuproptosis) but displayed a notable reduction in the expression of ATP7A (a copper efflux transporter) in the lung tissue of experimental MA-ALI/ARDS mice. Compared to the P. berghei ANKA-infected control group, mice that were administered DSF exhibited a remarkable increase in parasitemia/lung parasite burden, total protein concentrations in bronchoalveolar lavage fluid (BALF), lung wet/dry weight ratio, vascular leakage, and pathological changes in lung tissue. Strikingly, the experimental MA-ALI/ARDS mice with DSF treatment also demonstrated dramatically elevated copper levels, expression of SLC31A1 and FDX1, numbers of CD86+, CD68+, SLC31A1+-CD68+, and FDX1+-CD68+ macrophages, and messenger RNA (mRNA) levels of pro-inflammatory cytokines (tumor necrosis factor [TNF-α] and inducible nitric oxide synthase [iNOS]) in lung tissue, but showed a remarkable decrease in body weight, survival time, expression of ATP7A, number of CD206+ macrophages, and mRNA levels of anti-inflammatory cytokines (transforming growth factor beta [TGF-β] and interleukin 10 [IL-10]). In contrast, TTM treatment reversed these changes in the infected mice. Similarly, the in vitro experiment showed a notable elevation in the mRNA levels of SLC31A1, FDX1, CD86, TNF-α, and iNOS in iRBC-stimulated RAW 264.7 cells targeted with DSF-CuCl2, but triggered a remarkable decline in the mRNA levels of ATP7A, CD206, TGF-β, and IL-10. In contrast, TTM-CuCl2 treatment also reversed these trends in the iRBC-stimulated RAW 264.7 cells.

Conclusions: Our data demonstrate that the activation of cuproptosis with DSF aggravated the severity of MA-ALI/ARDS by partially inducing M1 polarization of pulmonary macrophages, while inhibition of cuproptosis with TTM contrarily ameliorated the severity of MA-ALI/ARDS by promoting macrophage M2 polarization. Our findings suggest that blockage of cuproptosis could be a potential therapeutic strategy for treatment of MA-ALI/ARDS.

杯状突变在调解实验性疟疾相关急性肺损伤/急性呼吸窘迫综合征严重程度中的作用。
背景:疟疾相关急性肺损伤/急性呼吸窘迫综合征(MA-ALI/ARDS)是恶性疟原虫感染的一种致命并发症,部分是由巨噬细胞的募集和极化引发的。据报道,铜暴露会增加感染疟疾的风险,而铜积累诱导的杯突症会引发 M1 巨噬细胞极化。据此推测,铜突变可能是 MA-ALI/ARDS 发病机制中的一个关键介质,但其潜在机制仍不清楚。本研究旨在探讨杯突在小鼠 MA-ALI/ARDS 严重程度中的作用:我们利用雌性 C57BL/6 小鼠感染 P. berghei ANKA 建立了 MA-ALI/ARDS 的实验模型,并用强效铜离子载体双硫仑(DSF)或铜离子螯合剂四硫代钼酸盐(TTM)处理这些动物。为了进一步研究其潜在机制,我们还用 DSF-CuCl2 或 TTM-CuCl2 靶向体外受感染红细胞(iRBCs)刺激的 RAW 264.7 巨噬细胞:结果:我们的研究结果表明,在实验性 MA-ALI/ARDS 小鼠肺组织中,铜的含量以及 SLC31A1(铜流入转运体)和 FDX1(杯突变的关键正调控因子)的表达量急剧升高,但 ATP7A(铜流出转运体)的表达量明显降低。与感染 P. berghei ANKA 的对照组相比,服用 DSF 的小鼠的寄生虫血症/肺寄生虫负荷、支气管肺泡灌洗液(BALF)中的总蛋白浓度、肺干湿重量比、血管渗漏和肺组织病理变化均显著增加。令人震惊的是,接受 DSF 治疗的实验性 MA-ALI/ARDS 小鼠肺组织中的铜水平、SLC31A1 和 FDX1 的表达、CD86+、CD68+、SLC31A1+-CD68+ 和 FDX1+-CD68+ 巨噬细胞的数量以及促炎细胞因子(肿瘤坏死因子 [TNF-α] 和诱导型一氧化氮合酶 [iNOS])的信使 RNA (mRNA) 水平也显著升高、但体重、存活时间、ATP7A 的表达、CD206+巨噬细胞的数量以及抗炎细胞因子(转化生长因子 beta [TGF-β] 和白细胞介素 10 [IL-10])的 mRNA 水平均显著下降。相比之下,TTM 治疗可逆转受感染小鼠的这些变化。同样,体外实验显示,在以 DSF-CuCl2 为靶标的 iRBC 刺激的 RAW 264.7 细胞中,SLC31A1、FDX1、CD86、TNF-α 和 iNOS 的 mRNA 水平显著升高,但引发 ATP7A、CD206、TGF-β 和 IL-10 的 mRNA 水平显著下降。相比之下,TTM-CuCl2 处理也逆转了 iRBC 刺激的 RAW 264.7 细胞的这些趋势:我们的数据表明,用 DSF 激活杯突活化可部分诱导肺巨噬细胞 M1 极化,从而加重 MA-ALI/ARDS 的严重程度;而用 TTM 抑制杯突活化则可促进巨噬细胞 M2 极化,从而改善 MA-ALI/ARDS 的严重程度。我们的研究结果表明,阻断杯突可能是治疗 MA-ALI/ARDS 的一种潜在治疗策略。
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来源期刊
Parasites & Vectors
Parasites & Vectors 医学-寄生虫学
CiteScore
6.30
自引率
9.40%
发文量
433
审稿时长
1.4 months
期刊介绍: Parasites & Vectors is an open access, peer-reviewed online journal dealing with the biology of parasites, parasitic diseases, intermediate hosts, vectors and vector-borne pathogens. Manuscripts published in this journal will be available to all worldwide, with no barriers to access, immediately following acceptance. However, authors retain the copyright of their material and may use it, or distribute it, as they wish. Manuscripts on all aspects of the basic and applied biology of parasites, intermediate hosts, vectors and vector-borne pathogens will be considered. In addition to the traditional and well-established areas of science in these fields, we also aim to provide a vehicle for publication of the rapidly developing resources and technology in parasite, intermediate host and vector genomics and their impacts on biological research. We are able to publish large datasets and extensive results, frequently associated with genomic and post-genomic technologies, which are not readily accommodated in traditional journals. Manuscripts addressing broader issues, for example economics, social sciences and global climate change in relation to parasites, vectors and disease control, are also welcomed.
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