Glaesserella parasuis infection triggers endoplasmic reticulum stress-mediated pyroptosis via PERK/eIF2α/ATF4 axis and metabolic reprogramming in porcine alveolar macrophages
Abstract Glaesserella parasuis, the causative agent of Glässer’s disease in swine, triggers severe systemic inflammation; however, the molecular mechanisms underpinning its pathogenesis remain incompletely understood. This study investigated the cellular and metabolic responses of porcine alveolar m...
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BMC
2025-07-01
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| Series: | Veterinary Research |
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| Online Access: | https://doi.org/10.1186/s13567-025-01580-2 |
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| author | Weili Feng Yu Han Wanyun Zhang Lei Wu Ao Zhou Liangyu Shi Jing Zhang |
| author_facet | Weili Feng Yu Han Wanyun Zhang Lei Wu Ao Zhou Liangyu Shi Jing Zhang |
| author_sort | Weili Feng |
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| description | Abstract Glaesserella parasuis, the causative agent of Glässer’s disease in swine, triggers severe systemic inflammation; however, the molecular mechanisms underpinning its pathogenesis remain incompletely understood. This study investigated the cellular and metabolic responses of porcine alveolar macrophage 3D4/21 cells to G. parasuis infection. Exposure to the pathogen significantly reduced cell viability and up-regulated pro-inflammatory cytokines (IL-6, IL-8, IL-1β, and TNF-α). Mechanistically, G. parasuis-induced apoptosis via up-regulation of Bcl-2-associated X protein (Bax) and cleaved Caspase-3, coupled with down-regulation of B-cell lymphoma-2 (Bcl-2). By contrast, pyroptosis was characterised by activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, Caspase-1 cleavage, and gasdermin D (GSDMD)-mediated membrane pore formation. Notably, infection provoked endoplasmic reticulum (ER) stress through the PERK/eIF2α/ATF4/CHOP pathway, as evidenced by ER expansion, ribosomal detachment, and mitochondrial damage. Treatment with the ER stress inhibitor 4-phenylbutyric acid (4-PBA) mitigated these alterations. Inhibition of PERK with GSK2656157 suppressed pyroptosis-related proteins (NLRP3, GSDMD, and Caspase-1) without altering apoptosis markers, indicating the existence of distinct regulatory pathways. Untargeted metabolomic profiling revealed extensive metabolic reprogramming, identifying 419 differentially expressed metabolites associated with pathways such as glutathione metabolism, glycerophospholipid metabolism, and arachidonic acid metabolism, underscoring their involvement in G. parasuis infection and immune modulation. Collectively, these findings demonstrate that G. parasuis undermines host defences by activating PERK-mediated ER stress to drive pyroptosis, while simultaneously inducing apoptosis and metabolic dysregulation through independent mechanisms. This study provides novel insights into G. parasuis pathogenesis and highlights the PERK pathway and metabolic regulators as potential therapeutic targets for mitigating Glässer’s disease. |
| format | Article |
| id | doaj-art-766b01b3cc79450591efda8970cc5cc5 |
| institution | Kabale University |
| issn | 1297-9716 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
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| series | Veterinary Research |
| spelling | doaj-art-766b01b3cc79450591efda8970cc5cc52025-08-20T03:43:30ZengBMCVeterinary Research1297-97162025-07-0156111410.1186/s13567-025-01580-2Glaesserella parasuis infection triggers endoplasmic reticulum stress-mediated pyroptosis via PERK/eIF2α/ATF4 axis and metabolic reprogramming in porcine alveolar macrophagesWeili Feng0Yu Han1Wanyun Zhang2Lei Wu3Ao Zhou4Liangyu Shi5Jing Zhang6Laboratory of Genetic Breeding, Reproduction and Precision Livestock Farming & Hubei Provincial Center of Technology Innovation for Domestic Animal Breeding, School of Animal Science and Nutritional Engineering, Wuhan Polytechnic UniversityLaboratory of Genetic Breeding, Reproduction and Precision Livestock Farming & Hubei Provincial Center of Technology Innovation for Domestic Animal Breeding, School of Animal Science and Nutritional Engineering, Wuhan Polytechnic UniversityLaboratory of Genetic Breeding, Reproduction and Precision Livestock Farming & Hubei Provincial Center of Technology Innovation for Domestic Animal Breeding, School of Animal Science and Nutritional Engineering, Wuhan Polytechnic UniversityLaboratory of Genetic Breeding, Reproduction and Precision Livestock Farming & Hubei Provincial Center of Technology Innovation for Domestic Animal Breeding, School of Animal Science and Nutritional Engineering, Wuhan Polytechnic UniversityLaboratory of Genetic Breeding, Reproduction and Precision Livestock Farming & Hubei Provincial Center of Technology Innovation for Domestic Animal Breeding, School of Animal Science and Nutritional Engineering, Wuhan Polytechnic UniversityLaboratory of Genetic Breeding, Reproduction and Precision Livestock Farming & Hubei Provincial Center of Technology Innovation for Domestic Animal Breeding, School of Animal Science and Nutritional Engineering, Wuhan Polytechnic UniversityLaboratory of Genetic Breeding, Reproduction and Precision Livestock Farming & Hubei Provincial Center of Technology Innovation for Domestic Animal Breeding, School of Animal Science and Nutritional Engineering, Wuhan Polytechnic UniversityAbstract Glaesserella parasuis, the causative agent of Glässer’s disease in swine, triggers severe systemic inflammation; however, the molecular mechanisms underpinning its pathogenesis remain incompletely understood. This study investigated the cellular and metabolic responses of porcine alveolar macrophage 3D4/21 cells to G. parasuis infection. Exposure to the pathogen significantly reduced cell viability and up-regulated pro-inflammatory cytokines (IL-6, IL-8, IL-1β, and TNF-α). Mechanistically, G. parasuis-induced apoptosis via up-regulation of Bcl-2-associated X protein (Bax) and cleaved Caspase-3, coupled with down-regulation of B-cell lymphoma-2 (Bcl-2). By contrast, pyroptosis was characterised by activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, Caspase-1 cleavage, and gasdermin D (GSDMD)-mediated membrane pore formation. Notably, infection provoked endoplasmic reticulum (ER) stress through the PERK/eIF2α/ATF4/CHOP pathway, as evidenced by ER expansion, ribosomal detachment, and mitochondrial damage. Treatment with the ER stress inhibitor 4-phenylbutyric acid (4-PBA) mitigated these alterations. Inhibition of PERK with GSK2656157 suppressed pyroptosis-related proteins (NLRP3, GSDMD, and Caspase-1) without altering apoptosis markers, indicating the existence of distinct regulatory pathways. Untargeted metabolomic profiling revealed extensive metabolic reprogramming, identifying 419 differentially expressed metabolites associated with pathways such as glutathione metabolism, glycerophospholipid metabolism, and arachidonic acid metabolism, underscoring their involvement in G. parasuis infection and immune modulation. Collectively, these findings demonstrate that G. parasuis undermines host defences by activating PERK-mediated ER stress to drive pyroptosis, while simultaneously inducing apoptosis and metabolic dysregulation through independent mechanisms. This study provides novel insights into G. parasuis pathogenesis and highlights the PERK pathway and metabolic regulators as potential therapeutic targets for mitigating Glässer’s disease.https://doi.org/10.1186/s13567-025-01580-2Glaesserella parasuisporcine alveolar macrophagesapoptosispyroptosisendoplasmic reticulum stressmetabolic reprogramming |
| spellingShingle | Weili Feng Yu Han Wanyun Zhang Lei Wu Ao Zhou Liangyu Shi Jing Zhang Glaesserella parasuis infection triggers endoplasmic reticulum stress-mediated pyroptosis via PERK/eIF2α/ATF4 axis and metabolic reprogramming in porcine alveolar macrophages Veterinary Research Glaesserella parasuis porcine alveolar macrophages apoptosis pyroptosis endoplasmic reticulum stress metabolic reprogramming |
| title | Glaesserella parasuis infection triggers endoplasmic reticulum stress-mediated pyroptosis via PERK/eIF2α/ATF4 axis and metabolic reprogramming in porcine alveolar macrophages |
| title_full | Glaesserella parasuis infection triggers endoplasmic reticulum stress-mediated pyroptosis via PERK/eIF2α/ATF4 axis and metabolic reprogramming in porcine alveolar macrophages |
| title_fullStr | Glaesserella parasuis infection triggers endoplasmic reticulum stress-mediated pyroptosis via PERK/eIF2α/ATF4 axis and metabolic reprogramming in porcine alveolar macrophages |
| title_full_unstemmed | Glaesserella parasuis infection triggers endoplasmic reticulum stress-mediated pyroptosis via PERK/eIF2α/ATF4 axis and metabolic reprogramming in porcine alveolar macrophages |
| title_short | Glaesserella parasuis infection triggers endoplasmic reticulum stress-mediated pyroptosis via PERK/eIF2α/ATF4 axis and metabolic reprogramming in porcine alveolar macrophages |
| title_sort | glaesserella parasuis infection triggers endoplasmic reticulum stress mediated pyroptosis via perk eif2α atf4 axis and metabolic reprogramming in porcine alveolar macrophages |
| topic | Glaesserella parasuis porcine alveolar macrophages apoptosis pyroptosis endoplasmic reticulum stress metabolic reprogramming |
| url | https://doi.org/10.1186/s13567-025-01580-2 |
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