TNF and Type I Interferon crosstalk drives 'regenerative inflammation' in IBD, perpetuating disease

Inflammatory bowel diseases (IBD) are complex disorders where epithelial dysfunction and maladaptive regeneration are increasingly recognized as critical, alongside immune dysregulation. While Tumor Necrosis Factor (TNF) is a key mediator of intestinal inflammation and a therapeutic target, it plays a dual role, supporting both immune activation and epithelial repair. Current anti-TNF therapies often fall short for a subset of patients, suggesting deeper, unaddressed mechanisms. This review explores how persistent TNF exposure, potentially reinforced by Type I Interferons (IFN-I), might convert adaptive epithelial repair into a chronic, disease-perpetuating state.

This review synthesizes a conceptual framework by integrating diverse lines of evidence to propose a novel mechanism for IBD persistence. The authors combined mechanistic insights from cellular and molecular studies, data from organoid-based models, and observations from clinical studies. Their approach was to build a comprehensive model of how TNF and Type I Interferons interact at the epithelial level, moving beyond a purely immune-centric view of IBD. The study did not involve new experimental data but rather a re-interpretation and integration of existing knowledge to form a new hypothesis.

The review proposes that while TNF-associated responses are generally adaptive during acute intestinal injury, supporting crypt repair and barrier restitution, chronic exposure, especially when reinforced by Type I Interferons (IFN-I), can become maladaptive. IFN-I signaling, suggested by experimental and translational studies, reinforces chemokine networks and transcriptional imprinting within the epithelium. This chronic TNF-IFN crosstalk is hypothesized to convert physiological repair into a sustained state termed 'regenerative inflammation.'

This 'regenerative inflammation' involves epithelial-derived signals that perpetuate immune cell recruitment and ongoing tissue remodeling, contributing to sustained pathology in a subset of IBD patients.

Such TNF-IFN-imprinted epithelial states are also hypothesized to be associated with reduced responsiveness to anti-TNF therapy, offering a potential explanation for treatment failures. The integrated evidence suggests a self-sustaining regenerative inflammatory circuit, highlighting the epithelial-immune interface as a critical, yet under-explored, driver of disease persistence.