Proteomics and cytokine array jointly reveal the role of macrophage proinflammatory shift in liver fibrosis in dairy cows with ketosis
Abstract Background Changes in macrophage function are crucial contributors to hepatic inflammation and fibrosis. However, the role of macrophages in the development of liver fibrosis in dairy cows with ketosis remains unclear. This study integrated proteomics and cytokine array approach to identify...
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BMC
2025-07-01
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| Series: | Journal of Animal Science and Biotechnology |
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| Online Access: | https://doi.org/10.1186/s40104-025-01219-4 |
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| author | Shiquan Zhu Moli Li Yihui Huo Qiqi Cao Zhaoju Deng Kui Li Yuxin He Jian Gao Chuang Xu |
| author_facet | Shiquan Zhu Moli Li Yihui Huo Qiqi Cao Zhaoju Deng Kui Li Yuxin He Jian Gao Chuang Xu |
| author_sort | Shiquan Zhu |
| collection | DOAJ |
| description | Abstract Background Changes in macrophage function are crucial contributors to hepatic inflammation and fibrosis. However, the role of macrophages in the development of liver fibrosis in dairy cows with ketosis remains unclear. This study integrated proteomics and cytokine array approach to identify the multifactorial and multicellular interaction effects driving liver fibrosis in dairy cows with ketosis and analyze the mechanism by which the proinflammatory shift in macrophages contributes to liver fibrosis. Results Histopathological analysis revealed liver injury, including severe steatosis, infiltration of inflammatory cells, an increase in lipid deposition, and a decrease in glycogen expression in ketotic cows. Moreover, the number of mitochondria considerably increased in hepatocytes. The activation of the dynamin-related protein 1/mitochondrial fission factor (DRP1/MFF) pathway induced excessive mitochondrial fission, and the inhibition of the nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) pathway led to the accumulation of intracellular reactive oxygen species (ROS). Proteomic analysis revealed the activation of extracellular matrix (ECM)-related functions and the NF-κB pathway in the liver, whereas cytokine array analysis revealed that the cytokine network was dysregulated. The accumulation of ROS triggered NF-κB nuclear translocation, inducing a proinflammatory shift in macrophages and liver inflammation. M1 polarization of macrophages promotes the release of proinflammatory mediators, which stimulated hepatic stellate cells (HSCs) activation, leading to ECM deposition, ultimately contributing to liver fibrosis. Conclusions To summarize, our study revealed the multifactorial and multicellular interaction effects driving liver fibrosis. Our results preliminarily showed that increased mitochondrial fission and inhibition of the Nrf2/HO-1 pathway are key factors in activating macrophages, which can lead to liver fibrosis in dairy cows with ketosis. |
| format | Article |
| id | doaj-art-c8c76ac69e994d1da9044a5143d5f22b |
| institution | Kabale University |
| issn | 2049-1891 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Animal Science and Biotechnology |
| spelling | doaj-art-c8c76ac69e994d1da9044a5143d5f22b2025-08-20T03:46:21ZengBMCJournal of Animal Science and Biotechnology2049-18912025-07-0116112010.1186/s40104-025-01219-4Proteomics and cytokine array jointly reveal the role of macrophage proinflammatory shift in liver fibrosis in dairy cows with ketosisShiquan Zhu0Moli Li1Yihui Huo2Qiqi Cao3Zhaoju Deng4Kui Li5Yuxin He6Jian Gao7Chuang Xu8National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural UniversityNational Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural UniversityNational Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural UniversityNational Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural UniversityNational Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural UniversityNational Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural UniversityNational Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural UniversityNational Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural UniversityNational Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural UniversityAbstract Background Changes in macrophage function are crucial contributors to hepatic inflammation and fibrosis. However, the role of macrophages in the development of liver fibrosis in dairy cows with ketosis remains unclear. This study integrated proteomics and cytokine array approach to identify the multifactorial and multicellular interaction effects driving liver fibrosis in dairy cows with ketosis and analyze the mechanism by which the proinflammatory shift in macrophages contributes to liver fibrosis. Results Histopathological analysis revealed liver injury, including severe steatosis, infiltration of inflammatory cells, an increase in lipid deposition, and a decrease in glycogen expression in ketotic cows. Moreover, the number of mitochondria considerably increased in hepatocytes. The activation of the dynamin-related protein 1/mitochondrial fission factor (DRP1/MFF) pathway induced excessive mitochondrial fission, and the inhibition of the nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) pathway led to the accumulation of intracellular reactive oxygen species (ROS). Proteomic analysis revealed the activation of extracellular matrix (ECM)-related functions and the NF-κB pathway in the liver, whereas cytokine array analysis revealed that the cytokine network was dysregulated. The accumulation of ROS triggered NF-κB nuclear translocation, inducing a proinflammatory shift in macrophages and liver inflammation. M1 polarization of macrophages promotes the release of proinflammatory mediators, which stimulated hepatic stellate cells (HSCs) activation, leading to ECM deposition, ultimately contributing to liver fibrosis. Conclusions To summarize, our study revealed the multifactorial and multicellular interaction effects driving liver fibrosis. Our results preliminarily showed that increased mitochondrial fission and inhibition of the Nrf2/HO-1 pathway are key factors in activating macrophages, which can lead to liver fibrosis in dairy cows with ketosis.https://doi.org/10.1186/s40104-025-01219-4Cytokine network dysregulationLiver fibrosisMacrophageMitochondrial fission |
| spellingShingle | Shiquan Zhu Moli Li Yihui Huo Qiqi Cao Zhaoju Deng Kui Li Yuxin He Jian Gao Chuang Xu Proteomics and cytokine array jointly reveal the role of macrophage proinflammatory shift in liver fibrosis in dairy cows with ketosis Journal of Animal Science and Biotechnology Cytokine network dysregulation Liver fibrosis Macrophage Mitochondrial fission |
| title | Proteomics and cytokine array jointly reveal the role of macrophage proinflammatory shift in liver fibrosis in dairy cows with ketosis |
| title_full | Proteomics and cytokine array jointly reveal the role of macrophage proinflammatory shift in liver fibrosis in dairy cows with ketosis |
| title_fullStr | Proteomics and cytokine array jointly reveal the role of macrophage proinflammatory shift in liver fibrosis in dairy cows with ketosis |
| title_full_unstemmed | Proteomics and cytokine array jointly reveal the role of macrophage proinflammatory shift in liver fibrosis in dairy cows with ketosis |
| title_short | Proteomics and cytokine array jointly reveal the role of macrophage proinflammatory shift in liver fibrosis in dairy cows with ketosis |
| title_sort | proteomics and cytokine array jointly reveal the role of macrophage proinflammatory shift in liver fibrosis in dairy cows with ketosis |
| topic | Cytokine network dysregulation Liver fibrosis Macrophage Mitochondrial fission |
| url | https://doi.org/10.1186/s40104-025-01219-4 |
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