{"title":"Role of cuproptosis in mediating the severity of experimental malaria-associated acute lung injury/acute respiratory distress syndrome.","authors":"Xinpeng Hou, Tingting Zhou, Qi Wang, Pinru Chen, Min Zhang, Lirong Wu, Wenbin Liu, Xiaobao Jin, Zhenlong Liu, Hua Li, Bo Huang","doi":"10.1186/s13071-024-06520-1","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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-CuCl<sub>2</sub> or TTM-CuCl<sub>2</sub> to further investigate the underlying mechanism.</p><p><strong>Results: </strong>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<sup>+</sup>, CD68<sup>+</sup>, SLC31A1<sup>+</sup>-CD68<sup>+</sup>, and FDX1<sup>+</sup>-CD68<sup>+</sup> 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<sup>+</sup> 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-CuCl<sub>2</sub>, but triggered a remarkable decline in the mRNA levels of ATP7A, CD206, TGF-β, and IL-10. In contrast, TTM-CuCl<sub>2</sub> treatment also reversed these trends in the iRBC-stimulated RAW 264.7 cells.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":19793,"journal":{"name":"Parasites & Vectors","volume":null,"pages":null},"PeriodicalIF":3.0000,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11489997/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Parasites & Vectors","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13071-024-06520-1","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PARASITOLOGY","Score":null,"Total":0}
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.
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.