# Inhibition of tumour necrosis factor alpha by Etanercept attenuates Shiga toxin-induced brain pathology

## TL;DR

Blocking TNF-alpha with Etanercept reduces brain damage caused by E. coli infection in a mouse model.

## Contribution

This study identifies TNF-alpha as a key driver of brain pathology in EHEC infection and shows that its inhibition mitigates neuroinflammation and microglial activation.

## Key findings

- Etanercept significantly reduced complement pathway activation and coagulation cascade changes in the brain proteome.
- Inhibition of TNF-alpha reversed microglial morphological changes to a healthy state.
- Angiopathy caused by Shiga toxin and LPS was significantly attenuated by TNF-alpha inhibition.

## 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.

The online version contains supplementary material available at 10.1186/s12974-025-03356-z.