Abstract
The gut mucosa is constantly challenged by a bombardment of foreign antigens and environmental microorganisms. As such, the precise regulation of the intestinal barrier allows the maintenance of mucosal immune homeostasis and prevents the onset of uncontrolled inflammation. In support of this concept, emerging evidence points to defects in components of the epithelial barrier as etiologic factors in the pathogenesis of inflammatory bowel diseases (IBDs). In fact, the integrity of the intestinal barrier relies on different elements, including robust innate immune responses, epithelial paracellular permeability, epithelial cell integrity, as well as the production of mucus. The purpose of this review is to systematically evaluate how alterations in the aforementioned epithelial components can lead to the disruption of intestinal immune homeostasis, and subsequent inflammation. In this regard, the wealth of data from mouse models of intestinal inflammation and human genetics are pivotal in understanding pathogenic pathways, for example, that are initiated from the specific loss of function of a single protein leading to the onset of intestinal disease. On the other hand, several recently proposed therapeutic approaches to treat human IBD are targeted at enhancing different elements of gut barrier function, further supporting a primary role of the epithelium in the pathogenesis of chronic intestinal inflammation and emphasizing the importance of maintaining a healthy and effective intestinal barrier.
Highlights
The gastrointestinal tract, from the beginning of extrauterine life, is chronically exposed to a huge burden of foreign antigens, various microorganisms, and toxic molecules
Any defect in these intestinal epithelial cells (IECs)-specific processes can cause a breakdown in gut barrier and a disruption of normal mucosal immune homeostasis that can potentially lead to uncontrolled chronic inflammation, such as that observed in inflammatory bowel disease (IBD)
A recent large GWA study, including more than 2300 cases and 5400 control subjects, identified novel epithelial-related susceptibility genes for UC [89]; this study found the greatest association with HNF4A, a gene encoding hepatocyte nuclear factor 4α, a transcription factor that regulates the synthesis of several tight junctions (TJs), adherens junctions (AJs), and desmosome proteins [90]
Summary
The gastrointestinal tract, from the beginning of extrauterine life, is chronically exposed to a huge burden of foreign antigens, various microorganisms, and toxic molecules. DEFECTS IN EPITHELIAL-SPECIFIC INNATE IMMUNE FUNCTIONS LEAD TO INTESTINAL INFLAMMATION Intestinal epithelial cells, located at the interface between the external environment and the internal mucosal immune system, must be able to mount early and appropriate defense responses against various pathogens in order to maintain homeostasis. Central to this process are innate immune receptor molecules, referred to as pattern-recognition receptors (PRRs), whose function is to sense highly conserved structures or pathogen-associated molecular patterns (PAMPs) present among several different pathogens [1]. Flagellinreactive Th1 cells isolated from C3H/HeJBir mice have the ability
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