This enzyme can hydrolyze not only SM, but also other choline phospholipids, including lysophosphatidylcholine, with reduction of lysophosphatidic acid, and PAF [15, 77]

This enzyme can hydrolyze not only SM, but also other choline phospholipids, including lysophosphatidylcholine, with reduction of lysophosphatidic acid, and PAF [15, 77]. events such as survival, proliferation, differentiation, and apoptosis. Indeed, the metabolism of complex sphingolipid includes enzymes involved in different signaling pathways, which lead to the formation of bioactive molecules, including ceramide (Cer) and sphingosine (Sph), as well as their 1-phosphorylated derivatives ceramide-1-phosphate (C1P) and sphingosine-1-phosphate (S1P). The role and impact of BMS 599626 (AC480) sphingolipids and sphingolipid-mediated signaling emerged in their relevance in intestinal disorders, when aberrations in their metabolism lead to an altered sphingolipid homeostasis. Herein, we review our current knowledge on the impact of sphingolipid disequilibrium on intestinal inflammation, focusing on inflammatory bowel disease (IBD). 2. Inflammatory Bowel Disease The term IBD encompasses a group of common chronic inflammatory disorders affecting the gastrointestinal tract [1]. The major types of IBD are Crohn’s disease (CD) and ulcerative colitis (UC). Despite some overlapping clinical features, these diseases are characterized by distinct inflammatory profiles, gut microbiota composition, and symptomatology [2, 3]. CD potentially affects any portion of the alimentary tract and is characterized by a discontinuous and ulcerous transmural inflammation, associated with complications (e.g., intestinal granulomas, obstructions, abscesses, strictures, and fistulas) [3]. In UC, a continuous inflammation involves only the superficial layers of the intestinal mucosa and is localized to regions of the gut most highly colonized by bacteria, specifically at the rectum BMS 599626 (AC480) and moving proximally along the large bowel [4]. The pathogenesis of IBD is usually complex (Physique 1) and Mouse monoclonal to SORL1 for many aspects remains unclear. The general hypothesis is usually that IBD develops as a result of a persistent alteration of intestinal homeostasis, leading to a perturbation of the balance between the intestinal mucosa and the gut microbiome [1]. Diverse factors, such as genetic, environmental, and immunologic variations, participate to and influence the onset and reactivation of this disease [4, 5]. There is compelling evidence that an inherited/acquired genetic predisposition that leads to barrier disruption and overreaction of the mucosal immune responses to enteric/environmental antigens are major factors contributing to the pathogenesis of IBD [6C8]. The dysregulated reaction of the mucosal immunity to normal intestinal microflora may be induced by defects in the epithelial barrier (increased intestinal permeability), adherence of bacteria, or expression of the defensins proteins. Open in a separate window Physique 1 The pathogenesis of IBD. Genetic, microbial, and environmental factors participate to disrupt the intestinal barrier. The defective mucosal integrity starts a complex vicious cycle that leads to, enhances, and perpetuates IBD. The conversation among intestinal epithelial cells (IECs), intestinal microbes, and local immune cells plays a crucial role in the maintenance of the intestinal homeostasis and is disrupted in IBD, leading to overreaction of the mucosal immune response to normal intestinal microflora. Indeed, a common histopathological feature of IBD is an excessive immune activation, characterized by an exaggerated infiltration of mast cells, monocytes/macrophages, and polymorphonuclear leukocytes into the intestinal epithelium. This overabundance of immune cells is usually accompanied by continuous and dramatic production of proinflammatory stimuli, including cytokines, growth factors, and adhesion molecules, as well as of inflammatory mediators (especially those of the eicosanoid family) and reactive oxygen species (ROS) [9, 10]. All this results in the development of a severe and pervasive inflammation that promotes and exacerbates IBD. 3. Intestinal Sphingolipid Equilibrium The small intestine is usually lined by a single layer of self-renewing IECs, which cover the surface of fingers-like projections called villi, and that of flask-like structures around the base of villi called crypts. The large intestine does not contain villi. Complex sphingolipids are present throughout the intestinal tract, with preferential localization in the apical membrane of polarized IECs, endowing its architecture with enhanced stability and digestive/absorptive capacity. Enterocytes of the small intestine are characterized by the selective abundance of SM and glucosylceramide (GlcCer), whose levels account for more than twofold that of the colonic mucosa and about 40% of total lipids [11]. The high content of sphingolipids in the small intestine is associated with selective enrichment and localization of several species in the apical membrane of the absorptive villous cells, which parallels the continuous process of mucosal cell differentiation throughout the crypt-villus axis [12]. Indeed, individual sphingolipids are differently distributed in villus and crypt cells, higher amounts of Sph, GlcCer, and GM3 being BMS 599626 (AC480) present in villi and Cer, trihexosyl-Cer, and GD3 ganglioside in crypts [13]. Sphingolipids have rapid turnover, and their levels are controlled by the balance between synthesis and degradation. As in most cells,.

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