Inhibition of tumour necrosis factor alpha by Etanercept attenuates Shiga toxin-induced brain pathology
Abstract Infection with enterohemorrhagic E. coli (EHEC) causes severe changes in the brain leading to angiopathy, encephalopathy and microglial activation. In this study, we investigated the role of tumour necrosis factor alpha (TNF-α) for microglial activation and brain pathology using a preclinic...
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| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2025-02-01
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| Series: | Journal of Neuroinflammation |
| Online Access: | https://doi.org/10.1186/s12974-025-03356-z |
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| author | Robin Christ Devon Siemes Shuo Zhao Lars Widera Philippa Spangenberg Julia Lill Stephanie Thiebes Jenny Bottek Lars Borgards Andreia G. Pinho Nuno A. Silva Susana Monteiro Selina K. Jorch Matthias Gunzer Bente Siebels Hannah Voss Hartmut Schlüter Olga Shevchuk Jianxu Chen Daniel R. Engel |
| author_facet | Robin Christ Devon Siemes Shuo Zhao Lars Widera Philippa Spangenberg Julia Lill Stephanie Thiebes Jenny Bottek Lars Borgards Andreia G. Pinho Nuno A. Silva Susana Monteiro Selina K. Jorch Matthias Gunzer Bente Siebels Hannah Voss Hartmut Schlüter Olga Shevchuk Jianxu Chen Daniel R. Engel |
| author_sort | Robin Christ |
| collection | DOAJ |
| description | Abstract Infection with enterohemorrhagic E. coli (EHEC) causes severe changes in the brain leading to angiopathy, encephalopathy and microglial activation. In this study, we investigated the role of tumour necrosis factor alpha (TNF-α) for microglial activation and brain pathology using a preclinical mouse model of EHEC infection. LC–MS/MS proteomics of mice injected with a combination of Shiga toxin (Stx) and lipopolysaccharide (LPS) revealed extensive alterations of the brain proteome, in particular enrichment of pathways involved in complement activation and coagulation cascades. Inhibition of TNF-α by the drug Etanercept strongly mitigated these changes, particularly within the complement pathway, suggesting TNF-α-dependent vasodilation and endothelial injury. Analysis of microglial populations using a novel human-in-the-loop deep learning algorithm for the segmentation of microscopic imaging data indicated specific morphological changes, which were reduced to healthy condition after inhibition of TNF-α. Moreover, the Stx/LPS-mediated angiopathy was significantly attenuated by inhibition of TNF-α. Overall, our findings elucidate the critical role of TNF-α in EHEC-induced brain pathology and highlight a potential therapeutic target for mitigating neuroinflammation, microglial activation and injury associated with EHEC infection. Graphical Abstract |
| format | Article |
| id | doaj-art-4ea2f65674564b76a5c4cd2e50960b55 |
| institution | Kabale University |
| issn | 1742-2094 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj-art-4ea2f65674564b76a5c4cd2e50960b552025-02-09T12:48:12ZengBMCJournal of Neuroinflammation1742-20942025-02-0122111410.1186/s12974-025-03356-zInhibition of tumour necrosis factor alpha by Etanercept attenuates Shiga toxin-induced brain pathologyRobin Christ0Devon Siemes1Shuo Zhao2Lars Widera3Philippa Spangenberg4Julia Lill5Stephanie Thiebes6Jenny Bottek7Lars Borgards8Andreia G. Pinho9Nuno A. Silva10Susana Monteiro11Selina K. Jorch12Matthias Gunzer13Bente Siebels14Hannah Voss15Hartmut Schlüter16Olga Shevchuk17Jianxu Chen18Daniel R. Engel19Institute for Experimental Immunology and Imaging, University Hospital EssenInstitute for Experimental Immunology and Imaging, University Hospital EssenLeibniz-Institut Für Analytische Wissenschaften, ISAS, E.V.Institute for Experimental Immunology and Imaging, University Hospital EssenInstitute for Experimental Immunology and Imaging, University Hospital EssenInstitute for Experimental Immunology and Imaging, University Hospital EssenInstitute for Experimental Immunology and Imaging, University Hospital EssenInstitute for Experimental Immunology and Imaging, University Hospital EssenInstitute for Experimental Immunology and Imaging, University Hospital EssenInstitute for Experimental Immunology and Imaging, University Hospital EssenLife and Health Sciences Research Institute (ICVS),, School of Medicine, University of MinhoLife and Health Sciences Research Institute (ICVS),, School of Medicine, University of MinhoInstitute of Molecular Medicine and Experimental Immunology, University Hospital BonnInstitute for Experimental Immunology and Imaging, University Hospital EssenSection Mass Spectrometry and Proteomics, Diagnostic Center, University Medical Center Hamburg-EppendorfInstitute for Experimental Immunology and Imaging, University Hospital EssenSection Mass Spectrometry and Proteomics, Diagnostic Center, University Medical Center Hamburg-EppendorfInstitute for Experimental Immunology and Imaging, University Hospital EssenLeibniz-Institut Für Analytische Wissenschaften, ISAS, E.V.Institute for Experimental Immunology and Imaging, University Hospital EssenAbstract Infection with enterohemorrhagic E. coli (EHEC) causes severe changes in the brain leading to angiopathy, encephalopathy and microglial activation. In this study, we investigated the role of tumour necrosis factor alpha (TNF-α) for microglial activation and brain pathology using a preclinical mouse model of EHEC infection. LC–MS/MS proteomics of mice injected with a combination of Shiga toxin (Stx) and lipopolysaccharide (LPS) revealed extensive alterations of the brain proteome, in particular enrichment of pathways involved in complement activation and coagulation cascades. Inhibition of TNF-α by the drug Etanercept strongly mitigated these changes, particularly within the complement pathway, suggesting TNF-α-dependent vasodilation and endothelial injury. Analysis of microglial populations using a novel human-in-the-loop deep learning algorithm for the segmentation of microscopic imaging data indicated specific morphological changes, which were reduced to healthy condition after inhibition of TNF-α. Moreover, the Stx/LPS-mediated angiopathy was significantly attenuated by inhibition of TNF-α. Overall, our findings elucidate the critical role of TNF-α in EHEC-induced brain pathology and highlight a potential therapeutic target for mitigating neuroinflammation, microglial activation and injury associated with EHEC infection. Graphical Abstracthttps://doi.org/10.1186/s12974-025-03356-z |
| spellingShingle | Robin Christ Devon Siemes Shuo Zhao Lars Widera Philippa Spangenberg Julia Lill Stephanie Thiebes Jenny Bottek Lars Borgards Andreia G. Pinho Nuno A. Silva Susana Monteiro Selina K. Jorch Matthias Gunzer Bente Siebels Hannah Voss Hartmut Schlüter Olga Shevchuk Jianxu Chen Daniel R. Engel Inhibition of tumour necrosis factor alpha by Etanercept attenuates Shiga toxin-induced brain pathology Journal of Neuroinflammation |
| title | Inhibition of tumour necrosis factor alpha by Etanercept attenuates Shiga toxin-induced brain pathology |
| title_full | Inhibition of tumour necrosis factor alpha by Etanercept attenuates Shiga toxin-induced brain pathology |
| title_fullStr | Inhibition of tumour necrosis factor alpha by Etanercept attenuates Shiga toxin-induced brain pathology |
| title_full_unstemmed | Inhibition of tumour necrosis factor alpha by Etanercept attenuates Shiga toxin-induced brain pathology |
| title_short | Inhibition of tumour necrosis factor alpha by Etanercept attenuates Shiga toxin-induced brain pathology |
| title_sort | inhibition of tumour necrosis factor alpha by etanercept attenuates shiga toxin induced brain pathology |
| url | https://doi.org/10.1186/s12974-025-03356-z |
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