First name
Ilaria
Last name
Spadoni
Year of Study
Thesis Title
Identification and characterization of the "gut vascular barrier"
Thesis Abstract
In order to protect the body from harmful environmental agents, the intestine has developed a physical barrier formed by the epithelium and a specialized immune system able to induce either tolerance against food antigens and intestinal flora or inflammatory responses against dangerous microorganisms.
Here, we describe a new barrier that we called the gut vascular barrier (GVB) that plays a fundamental role in controlling the spreading of molecules and bacteria to systemic sites. We found that intestinal endothelial cells (ECs), located beneath the epithelium, expressed the main components of tight and adherent junctions necessary to avoid paracellular trafficking of molecules. In addition, we observed the existence of a "gut vascular unit" whereby ECs were associated with enteric glial cells and pericytes, whose role in the establishment of the GVB remains to be analyzed.
We showed that GVB integrity could be modified by Salmonella typhimurium infection. Indeed, upon infection ECs up-regulated the expression of PLVAP, marker of damaged/immature vascular barrier, which correlated with a higher permeability of the endothelium. One way by which S. typhimurium could modify the barrier properties of the intestinal ECs was through the negative regulation of the Wnt/β-catenin signaling pathway. Indeed, we found that β-catenin activation was reduced upon infection in vitro. Consistently, Salmonella was incapable to modify ECs permeability and to spread systemically in mice where β-catenin was constitutively activated by genetic means only in vascular ECs. Furthermore, we demonstrated that Salmonella pathogenicity island-2 was involved in the regulation of Wnt/β-catenin signaling pathway in ECs.
Here, we describe a new barrier that we called the gut vascular barrier (GVB) that plays a fundamental role in controlling the spreading of molecules and bacteria to systemic sites. We found that intestinal endothelial cells (ECs), located beneath the epithelium, expressed the main components of tight and adherent junctions necessary to avoid paracellular trafficking of molecules. In addition, we observed the existence of a "gut vascular unit" whereby ECs were associated with enteric glial cells and pericytes, whose role in the establishment of the GVB remains to be analyzed.
We showed that GVB integrity could be modified by Salmonella typhimurium infection. Indeed, upon infection ECs up-regulated the expression of PLVAP, marker of damaged/immature vascular barrier, which correlated with a higher permeability of the endothelium. One way by which S. typhimurium could modify the barrier properties of the intestinal ECs was through the negative regulation of the Wnt/β-catenin signaling pathway. Indeed, we found that β-catenin activation was reduced upon infection in vitro. Consistently, Salmonella was incapable to modify ECs permeability and to spread systemically in mice where β-catenin was constitutively activated by genetic means only in vascular ECs. Furthermore, we demonstrated that Salmonella pathogenicity island-2 was involved in the regulation of Wnt/β-catenin signaling pathway in ECs.
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