Inhibition of tumour necrosis factor alpha by Etanercept attenuates Shiga toxin-induced brain pathology
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.
Authors
- Susana Monteiro (ORCID: https://orcid.org/0000-0002-3037-9635)
- Lars Borgards (ORCID: https://orcid.org/0009-0000-2362-4674)
- Stephanie Thiebes (ORCID: https://orcid.org/0000-0001-5320-3889)
- Devon Siemes (ORCID: https://orcid.org/0000-0003-1869-1930)
- Matthias Gunzer (ORCID: https://orcid.org/0000-0002-5534-6055)
- Philippa Spangenberg (ORCID: https://orcid.org/0000-0002-5593-5546)
- Hartmut Schlüter (ORCID: https://orcid.org/0000-0002-9358-7036)
- Olga Shevchuk (ORCID: https://orcid.org/0000-0003-1150-7344)
- Andreia G. Pinho (ORCID: https://orcid.org/0000-0001-8151-4860)
- Bente Siebels (ORCID: https://orcid.org/0000-0001-9183-0381)
- Jianxu Chen (ORCID: https://orcid.org/0000-0002-8500-1357)
- Daniel Robert Engel (ORCID: https://orcid.org/0000-0001-7301-353X)
- Julia K. Lill (ORCID: https://orcid.org/0000-0001-8514-529X)
- Hannah Voß (ORCID: https://orcid.org/0000-0002-0900-7183)
- Selina K. Jorch (ORCID: https://orcid.org/0000-0002-6356-5012)
- Jenny Bottek (ORCID: https://orcid.org/0000-0002-4418-6092)
- Robin Christ
- Nuno André Silva (ORCID: https://orcid.org/0000-0002-1061-1716)
- Shuo Zhao (ORCID: https://orcid.org/0000-0001-6172-0931)
- Lars Widera
Institutions
- Universität Hamburg (DE)
- University Hospital Bonn (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Essen University Hospital (DE)
- Leibniz Institute for Analytical Sciences - ISAS (DE)
- University of Minho (PT)
Publication Details
- Journal
- Journal of Neuroinflammation
- Published
- 2025-02-07
- DOI
- https://doi.org/10.1186/s12974-025-03356-z
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wings for Life
- Wings for Life
- Universitätsklinikum Essen
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Universität Duisburg-Essen
- Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen
- Fundação para a Ciência e a Tecnologia