Abstract
The small intestine has a high rate of cell turnover under homeostatic conditions, and this increases further in response to infection or damage. Epithelial cells mostly die by apoptosis, but recent studies indicate that this may also involve pro-inflammatory pathways of programmed cell death, such as pyroptosis and necroptosis. Celiac disease (CD), the most prevalent immune-based enteropathy, is caused by loss of oral tolerance to peptides derived from wheat, rye, and barley in genetically predisposed individuals. Although cytotoxic cells and gluten-specific CD4+ Th1 cells are the central players in the pathology, inflammatory pathways induced by cell death may participate in driving and sustaining the disease through the release of alarmins. In this review, we summarize the recent literature addressing the role of programmed cell death pathways in the small intestine, describing how these mechanisms may contribute to CD and discussing their potential implications.
Highlights
Inflammatory cytokines released by Th1, cytotoxic T lymphocytes (CTLs) (IFNγ, TNFα), activated dendritic cells and other antigen presenting cells (APC) (Type I IFNs) and activated macrophages (ROS) sensitize different cells, especially epithelial cells, to trigger intrinsic apoptosis
All the new Programmed Cell Death (PCD) could trigger the release of inflammatory factors, such as alarmins and IL-1β and IL-18, which may feed the inflammatory process. (Bottom Image): Potential effect of alarmins and IL-1β/IL-18 in Celiac disease (CD) mucosae
Pro-cytotoxic capacity of CTLs can be enhanced by the presence of IL-33, IL-1, high-mobility group box 1 protein (HMGB1) but especially IL-18
Summary
From the original concept of apoptosis as a unique form of immunologically silent programmed cell death, to proinflammatory necrosis, a broad spectrum of different pathways is known to develop in specific conditions. Other forms of PCD are not immunologically silent and are involved in driving and maintaining a variety of metabolic and inflammatory disorders. These pathways include necroptosis, pyroptosis and ferroptosis and they can result in the release of proinflammatory molecules such as alarmins (IL-33, HMGB1, IL-1α) and proinflammatory cytokines (IL-1β and IL-18) [1,2,3]. Inflammatory PCD enables the release of molecules such as IL-1β without cell death occurring [4]. Studying the molecular pathways involved in these processes is important in order to gain insight into the pathogenesis of inflammatory disorders and for the development of therapeutic interventions
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