Distinct Adaptive Repair Responses to Cell Death Modes in the Intestinal Epithelium

Inflammatory Bowel Disease (IBD) remains difficult to treat, partly because we do not fully understand how dying cells within the intestinal lining influence immune responses and tissue repair. Different types of cell death—apoptosis (non-inflammatory), necroptosis, pyroptosis (inflammatory)—occur in IBD, but how immune responses to them shape healing remains unclear. When intestinal epithelial cells die through apoptosis, dendritic cells (DCs) help maintain balance by producing molecules that suppress inflammation and promote regulatory T cells (Tregs), which aid repair. However, necroptosis and pyroptosis release signals that trigger inflammation. While inflammation is often thought to hinder repair, we hypothesize that these signals shape immune responses in ways that influence healing. Specifically, we propose that DCs interpret these signals and drive the formation of distinct Treg cell populations, each with unique repair roles. This idea challenges the paradigm that inflammation and repair are at odds, suggesting instead that certain inflammatory responses may help set the stage for recovery. Using innovative mouse models, we aim to uncover how DCs integrate signals from different types of cell death to direct tailored repair processes. By understanding these mechanisms, we hope to develop therapies that not only control inflammation but also promote lasting healing in IBD patients.